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Cholesterol
steriod ring system, an important part of membrane integrity, provides carbon platform with messages above and below rings (methyl or hydroxyl groups)
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Cholesterol absorption/transport
After absorption in the gut, transported to liver and tissues via chylomicrons
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Bile salts
cholesterol is broken down into bile salts by hydroxylases, excreted form of cholesterol
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Bile acids
return to the liver after reabsorption in the terminal ileum, recycled form of cholesterol
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Cholesterol biosynthesis
humans can synthesize up to 1g cholesterol per day
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Cholesterol ester
most cholesterol is stored as esters because you can store fatty acids on them, transported via lipoprotein
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Chylomicrons
water soluble, fat glob, apolipoproteins on surface allow for cell recogniton, cholesterol ester, free fatty acids, triglycerides in the core
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Biosynthesis of 1 mole of cholesterol
18 moles of aceytl CoA, 36 moles of ATP, 16 moles of NADPH
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Site of cholesterol biosynthesis
cytoplasm of hepatic liver cells, starts wth acetyl CoA
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Cholesteor biosynthesis pathway
Acetyl CoA (2C)--(HMG CoA reductase)-->mevalonate (6C)--->farnesyl pyrophosphate( 15 C)---> combine 2 farnesyl--->squalene (30C)--->7-dehydro-cholesterol
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Rate limiting enzyme for cholesterol biosynthesis
HMG CoA reductase-->takes ester and reduces it down to an alcohol (mevalonate) **IRREVERSIBLE
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HMG CoA reductase activity
Phosphorylated is inactive and non-phosphorylated is active
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Synthesis of HMG CoA reductase
Hepatic HMG CoA reductase synthetase--> stimulated by well fed state, inhibited by dietary cholesterol intake
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Statin drugs
inhibit HMG-CoA reductase to prevent cholesterol biosynthesis-->lower intracellular cholesterol and lowers apo B/E recpetor
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ACAT
turns cholecterol in cholesterol ester
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Regulation of cholesterol uptake via SREBP
Oxysterols (hydroxylated cholexterol) bind to Liver X receptor (LXR)-->upregulates SREBPs-->SCAP bring SREBP to protease-->cleaved by protease-->activates SREBP in gene expression
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Factors that increase intracellular cholesterol concentration
de novo biosynthesis, Hydrolysis of cholesterol esters (cleave esters), Dietary intake of cholesterol and uptake from chylomicrons, receptor mediated uptake of cholesterol containing lipoproteins (LDL)
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Factors decreasing intracellular cholesterol concentration
Inhibition of cholesterol biosynthesis, Downregulate the LDL receptor, Esterification of cholesterol by acyl-CoA, Release of cholesterol to HDL, Conversion of cholesterol to bile salts or steroid hormones
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Hormone activation of cholesterol biosynthesis
insulin and tri-iodo-->increases cholesterol biosynthesis, glucagon and cortisol-->decrease cholesterol biosynthesis
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Steroid hormones (3 classes)
C21 corticoids in adrenal cortex, C19 androgens in testis, C18 estrogens in ovary
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Steroid hormones in cell
penetrate plasma membrane, bind to cytoplasmic locasted receptors-->causes conformational change in transcription factors
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Polypeptides hormones in cell
can't cross plasma membrane->bind to cell surface receptor-->termed first messengers-->intracellualr effects are mediated by small molecules like cAMP
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Nitric oxide (NO)
vasodilator used for angina, nitro pakcets are nitrated glycerol molecules-->signal the relaxation of smooth muscle in blood vessels by stimulation of guanylate cyclase= changes in intracelluar Ca2+
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Phospholipase (PLA2)
cleaves specific phospholipis to generate lipids messengers (arachidonic acid, DAG)
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Arachidonic acid
C20 unsaturdated fatty acid-->lipid 2nd messenger or inflammatory messenger
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Eicsanoids
synthesized in membranes from AA, signal via G-protein receptors, made via COX1 and COX2 enzymes
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Leukotrienes
Made from AA via lipoxygenases, have roles in inflammation
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PLA2
cleaves DAG or phospholipid-->arachodonic acid
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COX1 and COX2
use arachodonic acid make prostaglandins thromboxane, prostacyclin
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lipoxygenase
use arachodonic acid make leukotrienes
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cytochrome P450
use arachodonic acid make HETE (CO/NO inhibit here)
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Prostaglandin synthesis
start with AA --> make PGG2--> use peroxidase to make PGH2
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Thromboxane
vasoconstrictors
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Prostacycline
Vasodilators
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Prostaglandins
Fever inducers (COX1 and COX2 convert AA to PGG2)
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NSAIDS
non selective COX inhibitors (aspiring, ibuprofen), block COX1 and COX2-->inhibits the synthesis of PGG2 from AA)
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Aspirin mode of action
irreversibly acetylates COX1 and COX2, reduces inflammation, blocks the production of thromboxane (vasoconstrictor and clot builder)
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Prednisone
Steroidal anti-inflammatory drugs, inhibit PLA2, block all eicosanoids from converting DAG and phospholipids---> Arachodonic acid
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Leukotrienes
type of eicosanoid not made form COX1 and COX2, inflammatory/vasoactive mediators, made from AA via the action of lipoxygenases (which add O to lipid chains)
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Deficiency in lipoxygenases
40% of myeloproliferative disorders-->reduced lipoxygenases activity and increased synthesis of thromboxane
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Leukotriene activation
AA uses 5-LO and FLAP to make HPETE--> becomes LTA4 uses enzyme LTA4 hydrolase--> LTB4 (power attractant for immune cells)
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LTB4
power attractant for immune cells, involved in ashmatic and allergic reactions
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Hypoglycemia
blood glucose levels low-->glucagon is released-->leads to the degradation of glycogen--> and gluconeogenesis--.synthesize glucose from small molecules
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Glucagon receptors
on liver and recetpros
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Insulin
increases glucose uptake and storage-->decreases cAMP-->dephosphorylates-->increase glycogen synthesis,fatty acid synthesis, decreasse gluconeogenesis
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Glucagon
increase in cAMP-->activates PKA-->phosphorylates-->increase glood glucose, gluconeogenesis
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Glycolysis
occurs in the cytoplasm
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Glycolysis in RBC and brain
sole source of ATP for RBC, total glucose oxidation supplies almost all the ATP for brain (fatty acids can't cross BBB)
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Glycolysis in Skeletal muscle
supplies almost all the ATP under aerobic conditions
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Glycolysis in Liver
function depends on nutritional and hormonal state (well fed vs. fasting state)
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GLUT transporters
GLUT1 in Brain and RBC, GLUT2 in intesinal epithelial, liver, GLUT4 in muscle and adipose tissue
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Glucokinase
first step in converting glucose-->gluc 6-P, high Km, low affinity for glucose, never saturated, can always take up glucose
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Hexokinase
first step in converting glucose-->gluc 6-P, low Km, high affinity for glucose, saturated all times
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Two steps that make ATP in
PEP and 1,3-BP have high energy bond that can drive the synthesis of ATP (only other molecule that does this is creatine phosphate)
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Overall reaction of glycolysis (Aerobic)
Glucose+ 2NAD+ + 2ADP + 2Pi--->2 pyruvate + 2 NADH + 2 ATP
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Overall reaction of glycolysis (Anaerobic)
Glucose + 2ADP + 2 Pi --> 2 lactate + 2 ATP
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Vitamin cofactor for NADH
Niacin
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Vitamin for FADH/FADH2
Riboflavin
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Vitamin for DNA and glucose breakdown (PDH)
Thiamine
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Vitamine for CoA (coenyme for PDH)
B5 Pantothenic acid
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Create ROS
Powerful odizing agent: NADPH Oxidase, superoxide dismutase, myeloperoxidase
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Types of ROS created
O2-, H2O2, HOCl
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Glucose 6 Phosphate Dehydrogenase (G6PDH) deficiency
most important enzyme in pentose phosphate pathway, primary regulation step,causes hemolytic anemia due to inability to detoxift oxidizing enzyme (in pentose phosphate)
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Lesch-Nyhan Syndrome (LNS)
deficiency is hypoxanthin-guanine phosphoribosyl transferase (HGPRT)-->overaccumulation of PRPP (substrate for step 2 in purine biosynthesis), X-linked disorder
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Glycolysis 4 main enzymes
Hexokinase, Glucokinase, PFK-1,PK
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Gluconeogensis site
liver
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Fasting hypoglecemia (gluconeogenesis)
overnight fasting begin gluconeogenesis
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Neonatal hypoglycemia (gluconeogenesis)
The first 2-3 h after birth, newborn uses gluconeogensis
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Alcoholic hypoglycemia (gluconeogenesis)
first intermediate in gluconeogenesis is oxaloacetate-->translocated to cytosol as malata where NAD+ is needed to regenerate oxaloacetate-->large amt of alcohol reduces NAD+
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Glycerol comes into gluconeogenesis at what step
enters at DHAP
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Lactate comes into gluconeogenesis at what step
enters at pyruvate
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Pyruvate carboxylase (PC)
in mitochondira, turns Pyruvate-->oxaloacetate, needs ATP + Biotin as CO2 carrier
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3 major carbon sources for gluconeogenesis
glucogenic AAs, Lactate, Glycerol
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Glucogenic amino acids
from degradation of skeletal muscle protein--only 2 of 20 cant be used for glucose synthesis--can enter back in as pyruvate or other places in TCA cycle
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AAs that can't be used for glucose synthesis
leucine and lysine
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Lactate in gluconeogenesis
from anaaerobic muscle of RBC-->LDH convers lactate to pyruvate-->goes into gluconeogenesis
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Glycerol in gluconeogenesis
3C compound from adipose tissue to liver-->to be converted back to glycerl-3P-->oxidation to DHAP-->goes into gluconeogenesis
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Kori Cycle
Lactate cycle to take lactate back to the liver to convert them back to glucose--uses enzyme LDH
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Alanine cycle
Takes alanine back to the liver to convert it back to glucose--uses enzyme alanine transaminase
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Glycogen
the energy storage polysaccharide in animals
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Tissue synthesis and storage
liver and skeletal muscle
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Glycogen torage capacity is limited by
glycogenin
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Insulin stimulates
glycogen synthesis
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Glucagon and epinephrine stimulate
glycogen breakdown (epinephrine triggers cAMP, epnephrine is important in muscle)
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Skeletal muscle only have _________ receptor for signaling glycogen breakdown
epinephrine (muscle doesn't have glucagon receptors)
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# of glucose residues in glycogen granule in muscle
60,000 (in liver there are more)
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Glycogen granule structure
polysaccharide core alpha 1,4 and alpha1,6 bonds, protein coat has all the enzymes to synthesize, degrade and regulate glycogen
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Glyogenin
the core protein at the center of glycogen core, only reducind end, everything else is non reducing
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Branching in glycogen
significant for break down, the more branch points you have the more effeicient in taking up glucose in hyper glycemia
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Enzyme that mucles lacks for the release of glucose
G6Pase
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Muscle glycogen
oxidizes glucose via glycolusis to cupply muscle with ATP for contraction-->does not release it into the bloodstream
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Liver glycogen
supplies blood with glucose between meals
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Glucose receptor in muscle
GLUT4
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Liver receptor in liver
GLUT2
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Phosphoglucomutase
Enzyme that converts Glucose-6 phosphate (G6P)-->Glucose-1 phosphate (G1P)
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Gout
condition caused by monosodium urate monohydrate (MSU) crystals in and around the tissues of joints,
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Hyperuricemia
elevated serum urate above 6.8 mg/DL
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Variations in serum urate levels
age (serum urate increases with age, gender (women get symptoms after menopause, men 10 yrs after puberty), diet (high in purines)
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3 clinical stages gout
stage 1; acute gouty arthritis, stage 2: intermittant gout, stage 3: chronic gouty arthritis
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Definitive Diagnosis
identification of MSU crystals in synovial fluid leukocytes
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Lesch Nyan syndrome
deficiency in HPRT-->leads to increase in PRPP, guanine and adenine-->increase urate levels, only incident of prepubescent gout
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Allopurinol
treatment for gout that blocks the activity of xanthine oxidase-->stops the conversion of purines to urate
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Best way to diagnose gout
take a sample of tophus fluid
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Testing synovial fluid for gout
order cell count, gram stain, crystal analysis
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Pentose phosphate pathway
occurs in the cytosol,, branches from glycolysis, generates pentose phosphates for synthesis of RNA and DNA, important for RBCs, generates NADPH (anabolic)
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NADPH in pentose phosphate
generated from pentose phosphate pathway found in liver, adrenal cortex, RBC, involved in the biosynthesis of fatty acid, cholesterol, steroid hormones, bile salts
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Hepatocyte cytoplasm ratio of NADPH/NADP+ and NADH/NAD+
NADPH/NADP+= 10/1 NADH/NAD+=1/1000
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Primary role of NADPH
reduction of glutathione (GSH), maintenance of reduced glutathione, fatty acid and steroid synthesis
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Glutathione
AN ANTIOXIDANT (made of: SH+ glycine + cysteine + glutamate) maintain membrane integrity in its reduced state
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RBC energy derivation
gets energy by converting glucose into two molecules of lactate-->gains 2 ATP
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How much of the glucose entering RBC is used for pentose phosphate pathway?
10%
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Are oxidative reaction reversible?
No, they are irreversible
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Are nonoxidative reaction reversible?
Yes
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Redox stage Pentose phosphate pathway
1. G6P (NADP+-->NADPH + Glucose-6 phosphate dehydrogenase) -->6-phosphogluconolactone, 2. 6-phosphogluconolactone (lactonase) --> 6-phosphoglucanate, 3. 6-phosphoglucanate is oxidatively decarboxylated (6-phosphogluconate dehydrogenase, NADP+-->NADPH)-->ribulose-5-phosphate
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Step 2 of pentose phosphate pathway
6-phophogluconolate (lactonase, NADP+-->NADPH)-->6-phosphoglucanate dehydrogenase, Irreversible and not rate limiting
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Glucose-6 phosphate dehydrogenase (G6PD) deficiency
Causes hemolytic anemia due to inability to detoxify agents (owing to insufficient amt of reduced glutathione)
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Variable level of G6PD deficiency
class 1 (very severe, 2%) --> class IV (none, 60-150%)
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Interconversion of pentose phosphate pathway
To create NADPH: transketolase and transaldolase convert carbon skeletons of 3 molecules of ribulose-5-phosphate -->form 2 molecules of Fru-6-P and one Glyceraldehyde-3-P
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Interconversion of pentose phosphate pathway
To create riboseL nonoxidative reactions can synthesize ribose-5-P from Glyceraldehyde-3-P
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Transketolase
Thiamine diphosphate (TPP) is cofactor for transketolase, need thiamine for pentose 5- phosphate production
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TPP
cofactor for transketolase, pyruvate carboxylase, alpha-ketoglutarate dehydrogenase (TCA cycle), brnached alpha keto acid dehydrogenase
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If you are deficient in thiamine
reduce TPP-->reduce the amount of NADPH synthesis via pentose-5 phosphate pathway
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Where does cholesterol biosynthesis occur?
cytoplasm of hepatic cells (liver)
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What is the rate limiting enzyme in cholesterol biosynthesis?
HMG CoA reductase
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Action of phospholipases
Cleave phospholipids-->make Arachadonic Acid
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Eicasanoids
synthesized in membrane-->made from AA-->signal via G-proteins made via COX 1 and COX 2
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Leukotrienes
made from arachadonic acid via lipoxygenases
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HETE
made from AA via cytochrome P450--> 20-HETE implicated in hypertension-->inhibited by NO/CO
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COX 1
cyclooxygenase 1, constituitive found in platelets, kidney and stomach
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COX2
inducible, responsible for imflammatory prostaglandin synthesis
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Nonselective COX inhibitors
NSAIDS-aspirin, tylenol-->irreversibly inactivates COX 1 and 2 by blocking PGG2-->block production of thromboxane (vasoconstrictor) and clot builder
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Selective COX 2 inhibitors
celecoxib and rofecoxib
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Steroidal anti-inflammatory drugs
Prednisone-->inhibits PLA2 from converting DAG to arachadonic acid
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5-lipoxygenase (5-LO)
used to convert AA to 5HPETE
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FLAP
used to convert AA to 5HPETE
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Activation of leukotrienes
Activated leukocytes-->send signals for PLA2 to cleave membrane phospholipids-->AA is liberates-->5-LO and FLAP convert AA-->5-HPETE--->LTA4---> converted by LTA4 hydrolase to LTB4
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mineralocorticoids
involved in mineral balance, retention of sodium, excretion of potassium, regulating blood pressure
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aldosterone
mineralocorticoid, stimulates sodium reabsorption and causes increase in blood pressure
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glucocorticoids
steroid hormones important for anti-inflammatory and stress responses, immunosuppresive
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cortisol
key glucocorticoid, regulates cardiovascular and metabolic function, including stimulation of gluconeogenesis
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pathway of cortisol synthesis
cAMP-->PKA-->phsophorylates 20-22 desmolase-->forms cortisol
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hormone responsible for cortisol release
ACTH
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hormone responsible for aldosterone release
Angiotensin II
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cyt450P
mixed function oxygenases, converts arachidonic acid-->20 HETE via oxidation
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pathway of aldosterone synthesis
angiotensin II--> DAG + IP3 (IP3 --> Ca2+)-->PKC-->phosphorylates 20-22 Desmolase-->forms aldosterone
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rate liminiting enzyme for synthesis of steroid hormones
20-22 desmolase, cleaves off all but 2 Cs of the side chain on the D ring of cholesterol, regulated by phosphorylation/dephosphorylation via the secondary messenger cAMP-->PKA
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what hormone is deficient in the case of the virilized baby girl
21-hydroxylase-->leads tot increased testosterone production--?decreased production of cortisol and aldosterone
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pathway of virilized baby girl
cells of adrenal cortex-->produce angionentsin II--> activates the production of aldosterone
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congenital adrenal hyperplasia
pituitary __>releases ACTH-->(regulated by corticaol feeding back and inhibiting productiond of ACTH)
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cause of salt wasting in the case of the virilized baby girl
decreased aldosterone production-->NA+ loss-->hyponatremic dehydration
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cause of hypoglycemia in virilized baby girl
21 hydroxylase deficiency causes lack of cortisol-->no gluconeogenesis-->drop in blood glucose-->hypoglycemia
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citic acid cycle
citrate-->isocitrate-->alpha-ketoglutarate-->Succinyl CoA-->Succinate-->Fumarate-->Malate (shuttle)-->Oxalacetate
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Products of citric acid cycle
NADH and FADH2-->for aerobic production of ATP
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Electon transport chain
generates bulk of ATP for maintaining homeostasis through oxidative phosphorylation
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Where does ETC occur?
Inner mitochondrial membrane
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ETC complexes
Complex I-IV on inner mitochodrial membrane + 2 electron shuttles (CoQ and Cyt C) + Complex V generates ATP but has no enzyme activity
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Complex I
NADH Q reductase-->transfer 2 electrons from NADH and proteins to CoQ
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Complex II
succinate DH + Glycerol phosphate DH + Fatty actl CoA DH (+ CoQ electron shuttle)-->2 electronsof FADHs passes on to CoQ along with 2 protons
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Conezyme Q (CoQ)
CoQ is small lipid soluble, diffues and shuttle electrons though membrane to compleX III
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Complex III
cytochrom bc 1 complex-->transfers electons to Cyto C
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Cytochrome C
Water soluble protein-->accepts electons from II and shuttles them to complex IV
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Complex IV
cytochrome oxidase-->uses Fe and Cu-->transfers electrons to O2-->1 molecule H2O produced for each molecules of NADH of FADHs oxidized-->4 electrons transferred=4H+-->O2-->2 H2O
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Reducing agent at step 1 electron transport chain
NADH
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Gout (cause)
monosodium urate monohydrate (MSU) crystals in and around the tissues of joints
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Gout characteristics
elevated serum urate (hyperuricemia >6.8 mg/dL), recurrent acute arthritic attacks, presence of MSU crystals inside synovial leukocytes, MSU aggregates deposited in and around joint, renal disease
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Hyperuricemia
>6.8 mg/dL, anyone with hyperuricemia is arisk for gout
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Variations in serum urate levels
age (older you get the higher they are), gender (women don't get symptoms until after menopause), diet (high in purines like meat, shrimp, animal products)
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3 clinical stages of Gout
preceded by asymptomatic hyperuricemia, Stage 1: Acute gouty arthritis, Stage 2: intermittant gout, Stage 3: chronic gouty arthritis
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Definitive Diagnosis
identification of MSU crystals in synovial fluid leukocytes, identification of MSU crystals from tophus
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Purine synthesis
purines made de novo from Ribose 5-P + ATP---(PRPP synthetase)-->PRPP-->IMP--->Inosine-->Hypoxanthine-->Xanthine---(xanthine oxidase)->Urate
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Adenine enters the PRPP pathway by which enzyme
Adenine phosphoribosyltransferase (APRT)
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Guanine and Hypoxanthine enter PRPP pathwya by which enzyme
Hypoxanthine-Guanine phosphoribosyltransferase (HGPRT)
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HPRT Salvage pathway
let you reuptake purines and recycle them
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Lesch Nyhan Symdrome
X-linked disorder (pre-pubertal boys) HPRT deficiency--> increase in PRPP, guanine, adenine, urate
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Allopurinol
treatment for gout, blocks at xanthine oxidase
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Why do gout attacks occur at night?
pKa (level at reactants=products) of uric acid is 6, at night when we are sleeping-->respiratory acidossi-->shifts products to less soluble side
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Synovial fluid analysis (for gout diagnosis)
gross appearance, order cell count and differential (look for neutrophils, microbiology culture, gram stain, crystal analysis if gout is suspected-->need resh specimen because solutes can dissolve
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Crystal analysis in gout
polarizing microscope with compensator (MSU found in 90% of acute attacks, lower percent chronically)--can differentiate from pseudogout
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Synovial fluid analysis in gout
normal=clear, slightly viscous, WBCs low, no RBCs, no crystals, negative culture, gout fluid=tubid, opqaue, lots of WBCs, negative gram and culture, MSU cyrstals, negative birefringence
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Medical problems with increased risk for gout
hypertension, obesity, high alcohol intake, high meat intake, hyperinsulinemia, metabolic syndrome
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Purine catabolized to one common free base ______
xanthine
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Final step in Purine metabolism
xanthine oxidized by xanthine oxidase to form uric acid
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Fatty acid oxidation (energy provision)
provides half the oxidative energy required for liver, kidney, heart and skeletal muscle
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Lipid metabolism (outline of steps)
Lipid mobilization (TAGs hydrolyzed in adipose tissue to fatty acids plus glycerol)-->transport FAs in blood to the tissues-->activation of fatty acids as CoA ester-->transport to mitochondria via carnitine shuttle-->metabolized to acetyl CoA
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Triacylglycerol (TAG)-->free fatty acids (FFA)
TAGs---(via DAG)---> glycerol + FFAs
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Chylomicrons
transport fats
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Lipoprotein
transfer TAGs made in liver
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Carnitine shuttle
needed for the transportation of long chain fatty (12-20) acidsfrom cytosol into mito matrix
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Methylmalonic acidemia
missing the methylmalonyl CoA mutase to convrt odd chain fatty acids to succinyl CoA-->huge build up of methylmalonyl CoA-->metabolic acidosis and developmental retardation
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Methylmalonic aciduria
unable to convert B12 to coenzyme form-->flood urine with methylmalonic acid-->huge build up of methylmalonyl CoA-->metabolic acidosis and developmental retardation
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Degradation of odd chain fatty acids
propionyl CoA---(biotin as Co2 carrier)-->methylmalonyl CoA---(B12 coenzyme form + methylmalonyl mutase)-->succinyl CoA--->citric acid cycle
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Degradation of even chain fatty acids
Beta-oxidation
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Phytanic acid & branched chain
alpha-oxidation of phytanic acid (releases CO2)-->now thiokinase can anneal CoA-->proceed to B-oxidation to make acetyl CoA OR propionyl CoA-->succinyl CoA
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Jamaican vomiting sickness
ackee plant contains hypoglycin-->inhibits medium and short chain dehydrogenases-->inhibits B-oxidations
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Carnitine deficiency
no carnitine=no carnitine shuttle=you can't do b-oxidation of long chain FAs-->nonketotic hypoglycemia because you can't produces muscle aches and weakness following exercise
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Zellweger Syndrome
absence of peroxisomes in liver and kidneys-->can't degrade very long chain FAs-->accumulation of long chain FAs in the brain
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PKU
defect in the enzyme phenylalanine hydroxylase which converts phenylalanine--> tyrosine ( unable to break down phenylalanine)-->build up toxic metabolites 2-hydroxyphenylacetic acid, phenylpyruvid acid, pneyllactic acid
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hypomorphic mutation of enzyme defiency
some activity, but loss of function
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null mutation of enzyme defiency
no enzyme
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Biotinidase deficiency
deficient in the enzyme that converts biocytin to biotin-->results in problem in the catabolism of branch chain amino acid
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Other enzyme realted deficiencies
disfunctional protein (hypomorphi or null), deficient cofactor (vitamin), deficient activator protein, deficient transcription factor
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Metabolis Basis of disease
deficiency of product-->substrate for th next reaction-->energy (ATP) OR toxic metabolites
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testing for enzyme deficiency in blood
serum amino acids, serum ammonia, acylcarnitine (tandem mass spec)
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testing for enzyme deficiency in urine
urinary amino acids (UAA metabolites in TCA cycles), urinary organic acids, urinary acylcarnitine (tandem mass spec), GAGs
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errors in mitochondrial fatty acid oxidation
autosomal recessive inherited, potentially fatal disorders, intolerant of exercise
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disease characteristics
severe hypoglycemia/poor ketogenesis, sudden infant death, intolerance-muscle disease, heart disease (especiallyin long chain fatty acids), fatty liver
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MCAD deficiency
most common (1/60-->1/100 people are carriers), autosomal recessive, point mutation in exon 11, high concentration of Mchain FAs, acyl carnitines, acyl glycines in plasma and urine
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Trifunctional protien
2 subunits (alpha and beta)
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Trifunctional protein alpha subunit (HADHA)
involved LCHAD
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Trifunctional protein beta subunit (HADHB)
ketoacyl CoA thiolase
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LCHAD deficiency in fetus
toxic baby syndrome can cause the build of of LCHAD in fetal circulation, late in pregnancy mother will develop HELLP syndrome
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HELLP syndrome
hemolysis, elevated liver enzymes, low platelets seen in pregnant mothers, caused by an LCHAD deficiency in the fetus
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gas chromatography-mass spectrometry
used to detect urinary organic acids in mitochondrial fatty acid oxidation disorders
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How to treat VLCAD deficiency?
give MCADs, bypass the block OR give triheptanoin (C7) triglyceride-->KBs can be produced from odd chain FAs
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Where are primary bile salts created?
cytoplasm of liver parenchymal cells
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Bile salts are used to...
emulsify fats (soap molecules, hydrophobic on one side hydrophilic on the other)
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At physiological pH bile salts are
mainly ionized
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Rate rate limiting enzyme for bile salt production
7-alpha-hydroxylase enzyme (CYP7A1)
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CYP7A1
rate limiting enzyme in bile acid production, installs the OH group at position 7
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Where are secondary bile salts created?
by bacterial enzyme cleave og primary bile salts in intestines
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What controls bile secretions?
hormones
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How do bile salts get back to liver?
portal vein
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How much bile acids pass through the bile duct each day?
30g
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How much of total bile is excreted in feces?
2%
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Where do statins inhibit?
HMG CoA reductase
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What makes gallstones?
bile supersaturated with cholesterol
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steroid hormones
made from cholesterol
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Corticosteroids
C21 steroid hormones (Ex.progesterone) made in the adrenal cortex
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Androgen
C19 steroid hormones (Ex.androgens) made in the testis
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Estrogens
C18 steroid hormones (Ex.estrogen) made in the ovary
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Steroid hormone excretion
preprocessed to be more water soluble then excreted via the kidney --> in urine
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Mechanism of action of steroid hormones
act via nuclear action
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Type I steroid hormones
act via cytoplasmic receptors to form steroid-receptor complex--->receptor dimerizes-->nuclear localization signal exposed-->complex enter nucleus and binds to SRE (specific response element)-->functions as transcription factor-->enhance/repress gene expression
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How do steroid-receptor complexes find DNA sequence?
Zinc Finger on the receptor feels the DNA to find the palandromic
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Why are glucocorticoid receptor zinc fingers differ from standard zinc finger?
it has four cysteine instead od 2 cysteines and 2 histidines
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insulin
synthesized in pancreatic beta cells, anabolic hormone-->acts to decrease glucose in the blood
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glucagon
synthesized in pancreatic alpha cells, catabolic hormone-->action to increase blood glucose
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Insulin synthesis
preproinsulin-->signal peptide cleaved=proinsulin---->C-peptide cleaved= insulin
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2 phases of insulin release
phase 1, five steps (glucose comes into B-cells-->glucose is phosphorylated-->glycolysis-->increase in ATP-->close ATP gated K channel-->depolarization-->open voltage gated Ca channels-->trigger insulin release
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Why is insulin response to oral glucose high than IV infusion
because GI hormones help to increase insulin secretion
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Insulin binding to membrane receptor in muscle/adipose
dimerizes tyr-kinase receptor-->autophosphorylates-->phosohporylates IRS1-->activated a lot of pathways-->recruits GLUT4 to membrane
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What enzyme does muscle lack?
Glucose-6-phosphatase-->can't release glucose in the bloodstream
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Is GLUT 2 insulin dependent/independent?
independent, it is always one regardless of insulin level
-
Is GLUT 4 insulin dependent/independent?
dependent, glucose transport in muscle and adipose tissue depends on insulin levels
-
What kinds of metabolism does insulin affect?
carbohydrate, lipid, protein, ALSO PROMOTES POTASSIUM UPTAKE
-
Does GLUT4 mostly reside intracellularly or on the plasma membrane?
intracellularly, 90% is inisde the cell waiting to be mobilized to plasma membrane
-
How much does insulin affect GLUT4 receptor recruitment to surface?
insulin doubles recruitment of GLUT-4 receptors to plasma membrane
-
In type II diabetes, what is the most important cause of insulin resistance?
Defective insulin signaling (also, decreased # and affinity of receptors)
-
How do Type II diabetes patients first present?
impaired glucose tolerance
-
What causes insulin resistance?
post-receptor signal transduction defects (defective tyr-kin, mutations in genes coding for IRS1, defective translocation of GLUT2 to cell membrane)
-
Glucagon
mobilizes glucsoe from every available fuel source, increases lipolysis and ketogenesis from acetyl CoA
-
Glucagon mode of action
binds to its own receptor via G-protein couple proteins-->activates Adenyl Cyclase-->activates cAMP cascade--> activates PKA-->phophorylates PFK2-F2,6BPase-->activates F2,6BPase-->stimulate gluconeogenesis
-
Does muscle has glucagon receptors?
No
-
How do you stimulate gluconeogensis in muscle?
Epinephrine stimulates glycogenolysis and gluconeogenesis (and inhibits glycolysis and lipogenesis)
-
What receptors does epinephrine bind to?
alpha and beta adrenergic
-
What is the key enzyme responsible for hyperglycemia with stress?
epinephrine
-
Foxo1 and Foxa2
fork-head winged-helices, transcription factors that promote gluconeogenesis, synthesis is regulaated by insulin
-
Foxo1
promotes gluconeogensis in the liver in the fasting states by inducing the PEPCK and G-6-Pase enzymes (insulin phosphorylates foxo1 to blocks gluconeogenesis)
-
Foxa2
regulates fatty acid oxidation in fasted state by induing genes encoding for enzymes of glycolysis, FA oxidation and ketogenesis (insulin phosphorylates foxa2 to inhibits FA oxidation)
-
Diabetes lab values
>126 mg/dL fasting glucose or >200mg/dL after glucose tolerance test
-
Normal lab values for blood glucose
<110 mg/dL
-
Impaired fasting glucose
110
-
Cori cycle
allows recycling of lactate (from muscle anaerobic glycolysis) back to glucose (in liver) via gluconeogenesis
-
Glucose-alanine cycle
allows recycling of alanine (from muscle proteolysis) back to glucose (in liver) via gluconeogenesis
-
Metabolism during stress
hypermetabolic state
-
Sympathetic nervous system drives response of stress via what hormones?
epinephrine, glucagon, cortisol-->stimulates catabolism (glycogenolysis, lipolysis, proteolysis)
-
Can stress induce insulin resistance?
yes-->glucocorticoid hormone (GLUCAGON) stimulate gluconeogenesis by encoding genes for G6Pase and PEPCK
-
Two main components of Diabetes
hyperglycemia and vascular complications
-
Vascular effects of diabetes
oxidative damage of the small (microangiopathy) and large (macroangiopathy) arteries via ROS and AGE products
-
Organs affected by microangiopathy
kidney (diabetic nephropathy) and retina (diabetic retinopathy)
-
Cause of cataracts in diabetics
caused by glycated proteins through sorbitol oxidation
-
Type II diabetes
insulin independent, insulin resistant caused by B-cell failure
-
Type I diabetes
caused by autoimmune attack of pancreatic B-cells (insulin-dependent)--> leads to fasting hyperglycemia
-
Symptoms of Type I diabetes
polyuria, polydypsia, ketonemia (increased blood ketone bodies), ketonuria, overproduction of acetoacetic acids, metabolic acidosis
-
Genetic component of Type I Diabetes
HLA genes on chromosome 6, siblings have 10% increased risk of Type I diabetes if their siblings are affected
-
Main complication of Type II Diabetes
macrovascular components-->leads to coronary artery disease
-
Amadori products
glycated hemoglobin, most highly studied (AGE) glycated proteins
-
AGEs
Advanced glycated endproducts-->bind to membrane receptor-->make ROS-->recruit inflammatory proteins and cytokines
-
Polyol pathway
glucose-->sorbitol
-
Diabetic neuropathy
caused by sorbitol build up in the brain/nerve tissue
-
How does insulin affect K
insulin increases cellular uptake
-
K levels in Diabetes
lack of insulin= K efflux from cells-->osmotic diuresis-->
-
Fat soluble vitamins
A,D,E,K-->stored in tissues (not as readily extracted from diet as watr soluble vitamins)
-
Vitamin A
stored in liver, 3 compounds: retinol, retinoic acid, retinal-->retinoic acid most active, visual pigment rhodopsin found in the rod cells of the retina
-
Pro-vitmain precursor to vitamin A
Beta carotene
-
Vitamin A deficiency
common most cause of blindness in the world (defective night vision-->prgressive keratinization and blindness)
-
Vitamin A excess
leads to bone loss, hair loss, hepatosplenomegaly. nausea, vomiting
-
Vitamin D
is really a hormone, usually only vitamin required in diet, produced by the action of UV light on provitamins (7 dehyydroxycholesterol)
-
Causes of Vitamin D deficiency
insufficient sunlight, increased vitamin D metabolism due to low calcium intake
-
Deficiency in Vitamin D results in...
Vitmain D deficieny Rickets as a result of deficiency of calcium mineral (low circulating calcium concentrations
-
Vitamin D excess
causes enhanced calcium absorption and bone reabsorption-->leads to hypercalcemia and calcium deposition-->develop kidney stones
-
Vitamin E
mixture of several compounds alled tocopherol and present in 90% of human tissue, richest sources are vegetable oils and nuts
-
Most abundant antioxidant
Vitamin E, prevents free radical damage by donating hydrogen to free radical
-
Vitamin E deficiency
neurological symptoms, hemolytic anemia, thrombocytosis
-
Vitamin K
necessary for blood coagulation, absorption of vitamin K depends on appropriate fat absorption ( like vitamin E), dietary sources green leafy vegetavle, dairy, veg oils
-
Vitamin K production
by intestinal microflora-->ensure dietary deficiency does not occur
-
Vitamin K deficiency
can occur rarely in newborns with bleeding disorders (given a shot of Vitamin K at birth because the gut of a newborn is sterile)
-
Vitamin K inhibitors
antithrombin drugs
-
Water soluble vitamins
with the exception of vitamin B12, the body has no storage capacity for water soluble vitamins, No toxicity associated with excess, any excess is excreted in urin
-
Vitamin B complex
Act as coenzyme, Not toxicity associated with excess
-
Thiamine (vitamin B1)
essential for carboxylation reaction and carbohydrate metabolism, deficiency associated with alcoholism and Beri-Beri disease
-
Thiamine deficiency
alcoholism and Beri Beri disease, early sign are loss of appetite, constipation and nausea
-
Wernicke Korsakoff psychosis
thiamine deficiency resulting in ataxia, neuropathy, loss of eye coordination
-
Riboflavin (vitamin B2)
associated iwth oxidoreductase, attached to sugar alcohol ribitol, found in oxidoreductases as FMN and FAD, required for energy metabolism
-
Riboflavn deficiency
causes inflammation of the mouth and tongue, scaly dermatitis-->Pellagra
-
How do you measure Riboflavin status
erythtrocyte glutathione reductase activity
-
Niacin (Vitamin B3)
required for NAD+ and NADP+ synthesis-->oxidoreductase reactions, synthesized from tryptophan in liver
-
Pyridoxine (Vitamin B6)
important in amino acid metabolism and participates as cofactor for amino acid metabolism especially transamination and decarboxylase
-
Pyroxidine deficiency
causes irritability, nervousness, depression-->leads to neuropathy, convulsions and coma
-
Biotin
Important in carboxylation reaction, lipogenesis, gluconeogenesis, catabolism of branched chain AAs, normally synthesized by intestinal flora
-
What can cause Biotin deficiency?
consumption of raw eggs can cause biotin deficiency because egg white protein, avidin, combine with biotin preventing its absorption
-
Panthotenic Acid (Vitamin B5)
part of CoA
-
Folic acid
important in single carbon transfer reactions such as methylation reactions in metabolism and gene expression
-
Folic acid deficiency
leads to hyperhomocysteinemia-->increased risk of cardiovascular disease
-
What vitamin plays a role in the synthesis of purine and pyrimidines
folic acid
-
Deficiency of what vitamin leads to megaloblastic anemia?
folic acid-->enlarged blast cells in bone marrow
-
Most common cause of folate deficiency
pregnancy--due to increased demand
-
Cobalmin (Vitamin B12)
Similar structure to heme, excpet Iron replaced by cobalt, participates in recycling of folates, found only in food of animal origin
-
tetrahydrofolate trap
megaloblastic anemia characteristic of B12 deficiency-->due to reduced folate and accumulation of methyl THF
-
Vegans are at risk for developing____deficiency
vitamin B12
-
Vitamin C
active form is ascorbic acid-->oxidised to generate vitamin E-->essential nutrient in humans-->fragile and easily destroyed, found in citrus fruits
-
What vitamin is involved in collagen synthesis?
Vitamin C
-
Vitmain C deficiency
causes scruvy-->hemorrhages, muscle weakness, soft/swollen/bleeding gums, poor wound healing
-
What vitamin deficiency compromises immune function
Vitamin C
-
How do vitamin B6, B12 and folic acid prevent cardiovascular disease?
by lowering homocystein concentration
-
Trace elements
metal ions required as active components in proteins
-
Zinc
affects growth, skin integrity, wound healing
-
Zinc deficiency
causes skin lesions, sexual impairment, loss of hair (in patients with burns, and renall damage)
-
Copper
copper scavenges oxidase and other ROS, associated with cytochrome oxidase and superoxidedismutase, also important in crosslinking collagen
-
Only was to excrete copper?
through bile--chronic excessive copper intake results in liver cirrhosis
-
What is required to incorporate iron into Hb?
Copper
-
Selenium
forms part of antioxidant enzyme glutathione reductase peroxidase
-
Selenium defciency
found in mushroom-->leads to hemolytic anemia
-
Acidic drugs
bound to albumin, small Vd (mostly in plasma), often hydrophilic, often renally excreted, less extensively metabolized
-
basic drugs
Bound to alpha1-acid glycoprotein, often lipophilic (distrubted more in tissue), usually metabolized (first pass)
-
Lipoprotein lipase disorder (Ia)
LPL gene defect, Autosomal recessive, increase in chylomicrons, find erruptive xanthoma, hepatoslpenomegaly, pancreatitis
-
Familial dysbetalipoproteinemia (III)
apoE gene defect, Autosomal dominant or recessive, increase in chylomicrons and VLDL remnants, symptoms: xanthomas, CHD, PVD
-
Familial hypercholesteromia (IIa)
defect in LDL receptor, autosomal dominant, increased LDL, symptoms include tendon xanthomas and CHD
-
Familial defective apoB-100 (IIb)
defect in apoB-100, autosomal dominant, increased LDL, symptoms include tendon xanthomas and CHD
-
Inherited disorders of Low HDL are _____
Rare
-
Apo-A1 deficiency would result in _______ HDL levels
low
-
Tangier Disease
ABCA1 deficiency-->results in low levels of HDL
-
Hypothyroidism causes an _______ in LDL
increase
-
What can increase HDL?
alcohol,exercise, estrogen
-
What can decrease HDL?
obesity, smoking, type II diabetes, malnutrition, anabolic steroid, beta blockers
-
What can increase Triglycerides?
autoimmune disease, type II diabetes
-
What can increase Lp (a)?
renal insufficiency, hypothyroidism, menopause, nephrosis
-
Atorvastatin (Lipitor)
statin, decrease LDL levels, increased HDL, decreases triglycerides
-
Gemfibrozil
Fibrate, for hypertriglyceridemia, functions as PPAR-alpha agonist, stimulate beta oxidation of FAs, stimulate lipoprotein lipase activity
-
Niacin
inhibits lipolysis by blocking hormonsensitive lipase, stops FFAs from being mobilized from adipocytes, inhibits triglyceride synthesis-->decrease synthesis of LDLs, INCREASE HDL, decrease Lp(a)
-
Niacin vs. Fibrates
both treat hypertriglycerimedia, use Niacin is patient is on Warfarin
-
Niacin pharmacokinetics
undergoes first pass metabolism, converted to NAD and other metabolites because excreted in urine
-
Niacin adverse effects
cutaneous flushing due to prostaglandin release-->corrected with administration of aspirin
-
omega 3 fatty acids for lipidemias
increase beta-oxidation , increase lipoproteinlipase activity, adjunct therapy in combo with other drugs
-
Cholestyramine
Bile acid binding resin, anion exchange resins that bind up bile acids and bile salts in small intestine
-
Bile acid binding resins
decrease LDL, can combine with statin, prevent reabsorption and enterohepatic recirculation of bile,indirect way of depleting the body of cholesterol
-
Drug interaction: bile acid binding resins
interfere with the absorption of anionic drugs, and fat soluble vitamins (ADEK)
-
Ezetimibe
inhibits the absorption of cholesterol at the brush border of the small intestine (adjunct) only effects exogenous cholesterol taken in by food (30-40%)
-
Pharmacokinetics Ezetimibe
oral, very water soluble, intestinal glucuronidation facilitates absorption (usually glucuronidation decreases absorption)
-
Noncompetitive inhibitors
grapefruit juice (DHB) and nifedipine
-
Which is the most frequently involved in drug metabolomics?
CYP 3A4
-
What else is HMG CoA used to make (besides cholesterol)?
ketone bodies
-
What enzyme is used on HMG CoA in KB synthesis?
HMG CoA lyase
-
How do you go back to HMG CoA in the cholesterol biosynthesis?
Transmethylglutaconate shunt (escape hatch)
-
How many moles of ATP are required to make 1 mol cholesterol??
36
-
How many moles of Acetyl CoA are required to make 1 mol cholesterol??
18
-
How many moles of NADPH are required to make 1 mole of cholesterol??
16
-
Where do you get the NADPH used in cholesterol biosynthesis?
Pentose phosphate pathway
-
What converts cholesterol into cholesterol ester (refrigerator)?
ACAT
-
What happens as a result of increased cholesterol intake in diet?
inhibiton of cholesterol biosynthesis and inhibition of LDL receptor
-
In the presence of sterol SCAP is ___________, transcription of cholesterol biosyntheis is _________, esterification of cholesterol is___________?
inhibited, downregulated, activated
-
What is SCAPs role in cholesterol biosynthesis
brings SREBP to the protease-->activates SREBP--->activates transcription of LDL receptor and HMG CoA reductase
-
What is an oxysterol
25-hydroxycholesterol
-
What binds to LXR?
oxysterols
-
What helps HDL bind peripheral cell?
apoA
-
What does ABCA1 do in cholesterol transport?
moves cholesterol from the peripheral tissue-->HDL
-
Steroid hormones vs. polypeptide hormones affect on gene transcription
Steroid hormones can directly effect gene transcription, whereas polypep can only indirectly affect gene transcription
-
Polypeptide hormones mechanism of action
Cannot cross membrane, must bind to cell surface receptors and initiate effects via second messengers (cAMP, Ca2+, etc)
-
Example of how small molecules can cross membrane
Nitric oxide
-
Nitri oxide mechanism of action
give angina patients glycerol trinitrate-->convert to NO-->NO stimulates guanylate cyclase-->changes intracellular Ca2+-->dilation of blood vessel
-
Arachidonic acid
C20 unsaturated fatty acid, lipid 2nd messenger or inflammatory messenger
-
Eicosanoids
second messengers synthesized in membrane from AA, signal via G-coupled proteins, made via COX-1 and COX-2 enzymes (prostaglandins, prostacylins, thromboxanes, leukotrienes)
-
Leukotrienes
Made from AA via lipoxygenases
-
phospholipase A2 (PLA2) is a enzyme that cleaves off what?
a fatty acid
-
Phospholipase A2 cleaves fatty acids off, which can be converted into ________ and ______________?
leukotriene and prostaglandins
-
Prostaglandins
eicosanoid, fever inducers
-
Thromboxane
eicosanoid, vascoconstrictors
-
Prostacyclins
eicosanoid, vasodilator
-
What converts arachidonic acid to PGG2 ( eventually leading to prostaglandins, prostacyclins, thromboxane)?
COX-1 and COX-2
-
What converts PGG2-->PGH2?
peroxidase
-
What converts arachidonic acid to leukotrienes?
lipoxygenases
-
What converts arachidonic acid to HETE?
cytochrome P450
-
What inhibits the conversion of arachidonic acid to HETE?
CO/NO
-
What are other functions of eicosanoids?
Regulate inflammation, regulate blood flow to organs, control ion transport, induce sleep, vasoconstriction, platelet aggregation
-
Where are eicosanoids snythesized
from AA in membranes
-
What drug inhibits the what enzyme in the conversion of phospholipids/DAG-->arachidonic acid?
Prednisone, enzyme: PLA2
-
Nonselective COX inhibitors
aspirin, ibuprofen, acetominophen (inhibit COX-1 constituitive, COX-2 constituitive)-->affects large organ system (renal GI)
-
Selective COX-2 inhibitors
celecoxib and rofecoxib, inhibit the inducible COX-2, specifically ontrol pain, fever, inflammation
-
How does aspirin, inactive COX1 and COX2?
irreversibly blocks COX1 and COX2 by acetylation, preventing the production of PGG2
-
COX-1
cyclooxygenase 1, constiutive, found in platelets, kidneys and stomach
-
Leukotrienes
inflammatory and vasoactive mediators, formed from cleaving arachidonic acid by lipoxygenases
-
5-lipoygenase (5-LO)
converts AA-->5-HPETE this makes-->leukotriene A4
-
FLAP
regulator of lipoxygenase enzymes, could be a drug targets
-
What kind of disorders are associated with reduced lipoxygenase activity?
40% of myeloproliferative disorders (leukemias)
-
What reactions are leukotrienes associated with?
asthmatic and allergic reactions
-
What does LTB4 attract?
neutrophils (chemoattractant)
-
What cells are equpped with LTA4 hydrolase?
neutrophils and monocytes
-
What do monocytes differentiate into in tissue?
macrophages
-
How do omega-6 and omega-3 differ in chemical structure?
omega-3 has a double bond at the 3 position, omega-6 has no double bond at the 3 position
-
Which is more saturated (with hydrogens) omega-3 or omega-6?
omega-6
-
Omega-3 is more _____________ than omega-6?
anit-inflammatory
-
What are the endproducts of omega=3 and omega-6 fatty acids?
prostaglandins and leukotrienes (less inflammatory for omega-3, more inflammatory for omega-6)
-
Can you convert omega-3 (good) to omega-6 (bad)?
yes
-
Good sources of omega-3?
flax seeds, salmon, walnuts, alpha-linolenic acid (ALA)
-
Typical US diet high in linoleic (omega 6) vs. linolenic (omega 3) (ratio)
10:1
-
Glucocorticoids
reduce inflammation by upregulating anti-inflammatory proteins, 2 classes (immunologic and metabolic), metabolic increase gluconeogenesis (Ie, cortisol)-->stimulate fat breakdown in adipose tissue to generate FFA
-
Mineralocorticoids
regulate water and salt balance (Na+ retention), aldosterone acts on the kidneys to activate reabsorption of sodium and passive reabsorption of water, active secretion of K, major function in blood pressure and blood volume
-
aldosterone
mineralocorticoid hormone, aldosterone produced in the adrenal gland and secretion mediated by angiotensin II (also by ACTH) and local potassium levels, that is activated by PKC
-
rate limiting step in steroid synthesis
conversion of cholesterol to pregenenolone via 20,22 desmolase-->this is limited by the supply of cholesterol in the inner membrane
-
main glucocorticoid
cortisol
-
main mineralocorticoid
aldosterone
-
How is 20,22 desmolase activated
via phosphorylation (cAMP-->PKA-->phosphorylates 20,22-desmolase)
-
How is 20,22 desmolase activated in cells that make cortisol?
ACHT->cAMP-->PKA-->phosphorylates 20,22-desmolase
-
How is 20,22 desmolase activated in cells that make aldosterone?
angiotensin II-->increase IP3 and DAG-->cAMP-->PKC-->phosphorylates 20,22-desmolase
-
Describe the role of cyt P-450 mixed function oxygenases?
in combination with NADPH, FAD, Fe3+, O2 to form hydroxylated product
-
What enzyme deficiency causes congenital adrenal hyperplasia?
21-hydroxylase
-
What is the cause of salt wasting in the case of the virilized baby girl?
The underactivation of renin (converts angiotensinogen-->angiotensin) because of a lack of aldosterone-->results in decreased sodium and water reabsorption by the kidneys
-
What vitamin is used to make NAD+
Niacin
-
Niacin ______ HDL levels
increases
-
What vitamin in used to make FAD+/FADH
riboflavin
-
Pyruvate---> Lactate is oxidation or reduction?
pyruvate is getting reduced (NADH gets oxidized-->NAD+)
-
Oxidative phosphorylation
electron transport chain
-
substrate level phosphorylation
glycolysis and succinyl CoA-->succinate (releases GTP)
-
catabolism
oxidative, exergonic
-
anabolism
reductive endergonic
-
When does the level of ATP in skeletal muscle decrease?
in extreme exercise conditions
-
How much ATP does the body under resting conditions
80-100g
-
Phosphocreatine
some energy generated from anaerobic splitting of a phosphate off of phosphocreatine-->maximum energy tield in about 10 seconds
-
ATPase
takes ATP-->ADP (releases energy)
-
Creatine kinase
regenerates ATP by: PCr + ADP--> Cr + ATP
-
Higher intensity exercise
relies mostly on carbs
-
Lower intensity exercise
relies more on fat
-
What is the primary fuel source for an ultra marathon?
mostly fats-->you have to slow down
-
What is the primary fuel source in the first 2 minutes of any exercise?
carbs (anaerobic)
-
High energy phosphate bonds
1,3 BPG, PEP, A third is creatine phosphate that has enough energy to synthesize ATP
-
Total oxidation of glucose gives you
H2O and CO2
-
Quickest type of regulation
allosteric
-
Rate limiting enzyme in glycolysis
PFK-1
-
What regulates PFK-1 in muscle?
AMP (activates), ATP and citrate (inhibits)
-
What regulates PFK-1 in liver?
F-2,6-BP
-
What inhibits Hexokinase
G6P
-
Liver isozyme of pyruvate kinase is inhibited by what?
covalent: phosphorylation by PKA, allosteric: ATP and alanine
-
AMP Kinase
allosterically activated by AMP-->know ATP is low-->activates pathways that generate ATP (B-oxidation of fatty acids, glucose transport)-->inhibits those that require ATP (fat synthesis, PCr, Cholesterol synthesis)
-
Fructose can bypass the regulatory steps in glycosis and enter as ________ and _________
Glyceraldehyde-3-P and DHAP
-
How does fructose go to DHAP?
Fructose-->Fructose-1-P--(F1P aldolase)--> DHAP
-
hereditary Fructose Intolerance
F1P aldolase deficiency-->build up in F1P-->decrease in available phosphate-->looks like G1P so acts as competitive inhibitor for glycogenolysis-->HYPOGLYCEMIA
-
Uridyltransferase deficiency
accumulate gal-1-P and galactose-->enlarge liver, jaundice, cataract formation, cataracts (build up of galactitol-->product of galactose in the lens)
-
Nonpermitted transition in conversion between energy sources
cannot convert FAT to CARBOHYDRATE
-
Cofactors required for Pyruvate dehydrogenase
TPP (B1), FAD (B2, riboflavin), NAD (B3, niacin), CoA (B5, panthothenate), lipoic acid
-
What does PDH release when converting pyruvate-->acetyl CoA?
NADH and CO2
-
PDH is a multienzyme complex, how is it regulated?
PDH kinase and PDH phosphatase
-
what is oxidative carboxylation?
blowing off CO2
-
Where is NAD+ needed in gluconeogenesis
it is needed in the malatae shuttle to convert malate back to oxaloacetate in the cytosol
-
3 types of hypoglycemia
fasting hypoglycemia, neonatal hypoglycemia, alcoholic hypoglycemia
-
Pyruvate Carboxylase
catalyzes first step in gluconeogenesis, converts pyruvate to oxaloacetate, happens in mitochondrial matrix
-
What is needed for Pyruvate Carboxylase (2 vitamins, 2 other things)
Biotin, B5, Acetyl CoA, ATP
-
PEPCK
converts oxaloacetate to PEP, happens in cytosol, regulation is mostly transcriptional response to glucagon-->CREB-->cAMP, allosteric inhibition by ADP
-
G-6-Pase
converts G-6-P to glucose (only in liver, NOT IN MUSCLE), happens in the smooth ER and regulated by transcriptiona (glucagon-->CREB-->cAMP)
-
McArdle's disease
deficiency in muscle glycogen phosphorylase-->abnormally high muscle glycogen because you are not breaking it down-->causes weakness, cramping, decreased serum lactate
-
von Gierke's disease
Deficiency in Glucose-6-phosphatase (G6Pase)-->glycogen accumulation in liver and kidney-->hypoglycemia, ketosis
-
Pompe's disease
Lysosomal alpha-1,4 glucosidase-->glycogen accumulation in lysosomes, early death, normal blood glucose, normal glycogen structure, heart
-
Cori's disease
deficiency in debranching enzyme-->abnormal glycogen with short outer chains, hypoglycemia
-
Andersen's disease
deficiency in Branching enzyme-->abnormal glycogen, having long unbranched chains, early death due to cardiac and liver failure
-
Her's disease
Deficiency in liver glycogen phosphorylase-->abormally high content in liver glycogen, mild hypoglycemia and ketosis
-
How are glycogen storage diseases treated?
Dietary restrictions (high protein, low carb)
-
Complement cascae
opsonization, phagoctosis, recruitment of other inflammatory cells, MAC complex
-
C3 convertase
involved in all 3 complement pathway
-
4 plasma mediated systems
Kinin, clotting, fibrinolytc, and complement
-
Coagulation cascade
Intrinsic and extrinsic involvve Factor X-->produces soluble fibrin
-
Plasmin iniaties degradation
To break down fibrin you use fibrinolytic pathway
-
Coagulation cascade
Intrinsic and extrinsic involvve Factor X-->produces soluble fibrin
-
To break down fibrin you use fibrinolytic pathway
Plasmin iniaties degradation
-
4 plasma mediated systems
Kinin, clotting, fibrinolytc, and complements
-
Factor XII
is synthesized in the liver: Hageman factor, Involves the cleavage of a few peptide bond to activate the clotting cascade and the kinin cascade
-
Acute inflammation
minutes to day, rapid onset, neutrophils (last 2-3 days in tissue), restoration
-
Chronic inflammation
weeks to years, prolonged duration, macrophages and lymphocytes (B and T cells), angiogenesis
-
Conditions associated with chronic inflammation
cardiovascular disease, obesity, type II diabetes, chrons disease
-
Innate Immunity
always present, always present, neutrophils and macrophages, natural killer cells
-
Adaptive Immunity
Normally silent, componets are lymphocytes (B and T), B lymphocytes generate antibodies and T lymphocytes, cytokines
-
Libby research on chronic inflammation
involves innate and adaptive immune system
-
The two cell types in inflammation
epithelial and mesenchyma; ce;;s
-
Main cytokines in chronic inflammation
TNF, IL-1 IFN-gamma
-
Inflammation in response to LDL
macrophages have a huge amount receptors for oxidized and glycated LDL
-
Adaptive connects to innate immunity
T helper cells release IFN-gamma and signals MF to send signals to pro-inflammatory cytokines
-
monounsaturated fats
lower LDL, do not lower HDL (olive oil, walnut oil, avocado)
-
polyunsaturated fats
lower LDL but also lower HDL (fish oil)
-
Omega-3 unsaturated fats
type of polyunsaturated fat, helps reduce the triglycerise
-
saturated fats
BAD! Increase LDL cholesterol
-
Mediterranean Diet
Leads 23% decreased of death risk, high fruit, potato, beans, nuts, seeds, whole grain bread, olive oil, wine, little dairy
-
PGE1 and PGE3
the less inflammatory prostalgin
-
PGE2
fever inducing prostaglandin
-
Pyridoxal-P
enzyme that participates in the cleavage reaction for glucogen phosphorylase
-
TPP deficiency
genetic defect, lacking TPP then you can't convert Pyruvate-->acetyl CoA, causes lactic acidosis
-
B vitamin deficiency
alcoholics and anorexia
-
In protein turnover
All amine groups ge converted to Glutamine or urea
-
What causes negative nitrogen balance
starvation, uncontrolled diabetes, infection, trauma
-
What causes positive nitrogen balance
pregnancy, lactation, growth
-
Marasmus
deficiency in proten and calories (chronic)
-
Kwashirokor
deficiency in protein (onset precipitated by increased demand) not necessarily lacking in diet could be inability in protein synthesis
-
Major differences between Kwashiorkor and Marasmus
Marasmus has muscle wasting, albumin is moderately diminished and no body fat, Kwashiorkor has Edema and Hepatomegaly in still has some body fat, severely diminished serum albumin, normal insulin and cortisol levels
-
What do transaminases use as an amino acceptor?
alpha-ketoglutarate
-
Maple syrup urine disease
autosomal recessive, Deficiency in BCKA DH, so you can't degrade BCAAs, you get elevation in BCAAs, keto-acids and alpha-hydroxyacids in urine, vomiting lethargy, severe brain damage
-
BCL2
anti-apoptotic protein, homologue of ced9, BCL2 is associated with mito and somehow associated with blocking the release of cytoC, overexpression in B Cell lymphoma
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BCL2 family
there are two types of proteinsin the BCL family, BH3 only and BH3+other, can be pro or anti apoptotic
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caspases
proteases responsible for apoptosis, analogue in C. elegans is ced-3 (but in humans there are 14 different caspases), they are cystein dependent aspartate directed proteases AspHole, exist as zymogen activated by cleavage
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What activates caspases
Apaf-1 (ced-4 homologue), ATP, cytochrome C (comprise the apoptosome)-->this starts the activation of the initiator caspase 9
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BAX
pro-apoptotic, in the BCL family-->cause the release of cytoC
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Pro-apoptotic proteins
put the helical tail in the active site, sterically occluding their own active site (like CDKs), and inactivating them
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Anti-apoptotic proteins
have an open, hydrophobic BH3 pocket, and are active
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In cell undergoing apoptosis
Hydrophobic pocket is occupied by the BH3 domain of a pro-apoptotic, frees up the pocket of pro-apoptotic protein-->get apoptosis
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Megaloblastic anemia
caused by a dietary deficiency of folate or B12
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Aerobic glycolysis generates
2 pyruvate, 2NADH, 2ATP
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Anaerobic glycolysis generates
2 lactate and 2 ATP
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What enzyme in glycolysis requires NAD+
Glyceraldehyde-3-P
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Lactate dehydrogenase
used NADH to convert pyruvate to lactate-->generates NAD+
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Physical inactivity leads to a _________ in protien synthesis
decrease (50% by 14 days)
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Stress/burn/trauma leads to a ___________in protein synthesis, a ________ in protein degradation, with an overall net________
increase in synthesis, increase degradation, overall net decrease in protein
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Physical inactivity leads to a ______________ protein balance
negative
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Stress/trauma/burn leads to a ________________ protein balance
negative
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Cortisol generates a _______________ response of muscle
catabolic
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Cortisol cause _____________ in blood sugar resulting in _____________
increase, hyperglycemia
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Stress response in burns results in patients being ____________
hypermetabolic
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Branched chain amino acid (BCAA) transaminase
converts (valine, leucine, isoleucine) BCAA-->BCKA
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Branch chain ketoacid (BCKA) dehydrogenase
converts BCKA to BCKA analogues (propionyl CoA, acetyl CoA, acetoacetyl CoA)
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To ameliorate loss of lean body mass in bedrest supplement with_________
essential amino acids
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Hemolytic anemia caused by deficieny in _________________, blood smear includes_____________
G6P DH, Heinz bodies
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G6P DH
most common human enzymes deficiency
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G6P dehydrogenase
PPP, converts G6P-->phosphogluconolactone, IRREVERSIBLE
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Lactonase
converts 6-phosphogluconolactone-->6-phosphogluconate, IRREVERSIBLE
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6-phosphoglucanate dehydrogenase
converts 6-phosphogluconate--> ribulose 5-P
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Carnitine enzyme deficiencies
HYPOGLYCEMIA IS A COMMON SYMTPOM
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PPAR-alpha
transcription factos for fatty acid oxidation, targeted by Fibrates--fibrates are a PPAR agonist
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Beta-oxidation chain enzymes
VLCAD, LCAD, MCAD, SCAD
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Most common beta-oxidation enzyme deficiency
MCAD, on exon 11
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Mitochondrial trifunctional protien
HADHA alpha subunit, HADHB beta subunit, LCHAD on HADHA
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LCHAD activity
involved in HELLP syndrome, on the HADHA alpha subunit
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HELLP
hemolysis, elevated liver enzymes, low platelets, LCHAD deficiency in the toxic baby
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Treatment fo rmitochondrial beta oxidation disorders
mostly nutritional, goal to stabilize day to day, avoid catabolic events
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If have VLCAD deficiency
Try to supplment diet with medium-chain triglycerides
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SCAD deficiency symptoms
can't stay warm because these control the white/brown fats
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Anaplerosis and metabolic therapy
anabolic process, replenishing the pool with odd chain FAs
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what is the rate limiting enzyme in bile synthesis
7-alpha hydroxylase (CYP7A1)
-
What do bacteria use to convert primary bile acids to secondary bile acids?
peptidases
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Bile secretion is controlled by hormones
cholecystokinin
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How are steroid hormones are excreted?
after pre-processing in the liver--> excreted via the kidney in the urine
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What kind of binding domain to steroid hormones use?
zinc finger (2 zinc fingers because recptors dimerize
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How do steroids act once in the cell?
steroid hormones bind to receptor which binds specific response elements (transcription factors)
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How do steroid zinc fingers differ from standard?
have 3 cysteine residues instead of 2 cysteine 2 histidine
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Are steroid receptor motfis (DNA binding domains) are conserved?
True
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Insulin synthesis
Pancreatic beta cells-->formed as pre-proinsulin-->signal peptide cleaved-->proinsulin-->C-protein cleaved-->insulin
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What organelle synthesizes insulin
RER of pancreatic Beta cells
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What is a good marker for Beta-cell function?
C-peptide
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How is insulin release in Beta cell?
Glucose comes in through GLUT2-->phosphorylated by Glucokinase-->increase in ATP--> close ATP-gated K channel-->depolarizes cell--> Opens Ca2+ channels-->triggers release of insulin
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What aminoacids stimulate insulin?
leucine, arginine, lysine
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GI hormones that potentiate insulin secretion
GIP, cholecystokinin (also signals release of bile), GLP-1, and VIP
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In severe hypoglycemia why is there a higher oral glucose repsonse than IV?
Because IV would bypass the GI hormones that potentiate insulin secretion
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How are GLUT4 receptors recruited to cell membrane?
glucose binds insulin receptor--->tyr-kin-->IRS-->GLUT 4 brough to membrane
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Insulin does what to potassium levels in cells?
increases K uptake in cells
-
Insulin resistance is due to
post-receptor signaling transduction defects, defective insulin signaling
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This mineral plays an important yet indirect role in antioxidant function as part of glutathione peroxidase
selenium
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Increasing intake of this mineral can help offset the negative effects of a high sodium intake
Potassium
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Vitamin that humans and primates are among the few mammals that can't synthesize
Vitamin C
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Niacin can be made in the liver from which amino acid high in turkey
Tryptophan
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Newborns are given a shot of this vitamin at birth
Vitamin K
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This vitamin is the leading cause of blindness worldwide
Vitamin A
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Pantothenic acid is part of this compound that is common in the metabolism of three energy producing macronutrients
Acetyl CoA
-
To assess riboflavin status the activity of erythrocyte glutathione reductase is measured because it requires this coenzyme
FAD
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Vitamin important in most carboxylase reactions of metabolism
Biotin
-
Status of this vitamin can be assessed by measuring transketolase activity in the erythrocyte
Thiamin/TPP
-
This vitamin helps to keep homocysteine levels down
Folic acid- B12 (homocysteine+methylTHF-->mehtionine +THC)
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This vitamine prevent free radical damage by donating its hydrogen ion to the free radical
Vitamin E
-
This vitamin is derived from a steroid
Vitamin D
-
This vitamin plays an important role in blood clotting
Vitamin K
-
Supplement companies might promote vitamin C as a "fat burner" because it is the key reducing agent in this carrier
Carnitine
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This vitamin has been used to treat hypercholesterolemia
Niacin
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Supplements can not exceed 400mcg of folate because megadoses of folate mask a deficiency in this vitamin
B12
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Elderly patients and anyone with suppressed stomach acid secretion may lack intrinsic factor and will therefore need a supplement of this vitamin
B12
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Vegan who consumes no fortified food products is at greatest risk for this vitamin deficiency
B12
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Unlike most water soluble vitamins, this one can be stored in the body for long periods of time
B12
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Sodium is added to sports drinks to prevent this condition often experienced by long distance athletes
Hyponatremia- people drink lots of water, but not sodium, also gives credit for electrolytes
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Because of its role in improving insulin function, this mineral supplement is said to increase lean body mass
Chromium
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Due to its role in muscle contraction, many people takes this mineral supplement to help prevent muscle cramps during exercise
Calcium
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If you over cook your vegetables you may lose this entire class of vitamins
Water soluble/B vitamins are susceptible to damage by high heat while cooking
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Vitamin C is often added to food as a preservative because of its role as this
antioxidant
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This water soluble vitamin part of electron carried FAD is damaged easily by light and explains why milk is not packaged in clear bottles
riboflavin
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Every amino acid transaminase or decarboxylase requires this B vitamin
Pyridoxine B6
-
What enzyme requires Pyridoxal P?
glycogen synthase and transaminase
-
This macro mineral is part of ATP
Phosphorous
-
A vitamin made from cholesterol
Vitamin D
-
Beri Beri is caused by a lack of this water soluble vitamin
Thiamin
-
Vitamin C is often added to food as a preservative because of its role as this
Because of its role as an antioxidant
-
A patient reports complaining of shortness of breath when exercising and all over fatigue. This is the first disease to look into
Anemia
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Megaoblastic anemia
deficiency in B12-->prevents production of folate
-
Wilsons disease is an autosomal recessive disease leading to accumulation of this mineral/metal (part of cytochrome c oxidase) in the liver and brain
Copper
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