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What is the Pentose Phosphate Pathway's main regulator, the main enzymes, and products?
Regulator is NADP/NADPH
Glucose 6 phosphate-> glucose 6-phosphate dehydrogenase-> 6-phosphogluconolactone-> Lactonase-> 6-phosphogluconate-> 6-phosphogluconate dehydrogenase-> 2 x NADPH+ and ribulose -->Ribose 5-phosphate or 2 fructose 6-phosphate and glyceraldehyde 3-phosphate
Depends on requirements of cell
What is a Glucose 6-phosphate dehydrogenase deficiency?
Can't use the Pentose Phosphate Pathway.
Inability to Reduce glutathione -> little antioxidant protection
How is lactose produced?
In presence of prolactin
UDP-galactose + glucose -> beta-galactosyltransferase alph-lactalbumin -> lactose
NO sucrose, maltose, or fructose involved.
How is Gluconeogenesis regulated?
Main step is at the enzyme Fructose 1,6 bisphosphase
Stimulated by Citrate
Inhibited by Fructose 2,6 0 bisphosphate
Inhibited by AMP
Insulin suppresses gluconeogenesis when not needed.
What are the 3 different steps in Gluconeogenesis compared to glycolysis?
Pyruvate-> Pyruvate Carboxylase-> oxaloacetate->
PEP carboxylase-> phosphoenol pyruvate ... Fructose-1,6-bisphosphatase
In liver, glucose 6- phosphatase can release glucose into blood.
Why is Acetly CoA important?
Intermediate in many pathways
Can be made from carbohydrates, fatty acids, or amino acids.
Substrate for TCA or precursor to fatty acids, ketone bodies, and Cholesterol
What are the three enzymes of the PDH complex?
What coenzymes and substrates are needed for pyruvate decarboxylase?
TPP - thiamine pyrophosphate
What are the coenzymes and substrates needed for dihydrolipoyl transacetylase?
Substrates - Hydroxyethyl-TPP and CoASH(made with pantothenic acid)
Coenzyme - Lipoamide
What are the coenzymes and substrates for dihydrolipoyl dehydrogenase?
Reduced lipoamide and FAD and NAD+
What is pyruvate translocase?
The PDH complex is in the mitochondrial matrix, so it needs the pyruvate translocase to transport it across the mitochondrial membrane.
How is PDH complex regulated?
End Product Inhibition - acetyl-CoA and NADH
Allosteric inhibition via phosphate group(less active when phosphorylated)
What are the enzymes in the Citric Acid Cycle? (Starting with Acetyl-CoA)
Acetyl-CoA + oxaloacetate ->citrate synthase->citrate
Citrate->cis-acontitate ->Aconitase -> isocitrate
Isocitrate -> Isocitrate dehydrogenase ->a-ketoglutarate
a-ketoglutarate + CoASH-> a-ketoglutarate dehydrogenase complex -> succinyl-Coa
Succinyl-CoA -> Succinyl-CoA synthetase -> succinate + GTP
Succinate -> Succinate dehydrogenase -> Formate
Formate -> Formase -> Malate
Malate -> Malate dehydrogenase -> Oxaloacetate
What anaplerotic reaction involves pyruvate carboxylase?
Creation of Oxaloacetate from pyruvate.
How are the following enzymes regulated?
Citrate Syn - inhibited by ATP, NADH, succinyl-CoA, and Fatty acyl-coa
Iso-Cit Syn - activated by ADP, inhibited by NADH (product)
A-KG D complex - inhibited by succinyl-CoA and NADH (products)
What is the result of reduced PDH complex activity?
Reduction of pyruvate by NADH to lactate.
More lactic acid -> serum lactic acidemia
What causes Beri Beri and what is it?
Thiamine deficiency (no TPP)
Muscle atrophy and weakness.
Dry and Wet(edema, cardia failure) versions
Which of the complexes in the ETS are proton pumps?
Enzymes I, III, and IV
What is the procession of an electron down the ETS?
NADH or FADH2 -> Coenzyme Q -> Cytochrome C -> H2O
What are the effects of uncouplers and inhibitors of the ETS and some examples?
Inhibitor - CO and Cyanide. No reduction to H2O so electrons can go anywhere.
Uncoupler - DNP - alternative route so ATP synthesis does not occur. Excessive heat production.
Inhibitors will lead to build up of lactic acid due to fermenation for ATP needs.
How does the ATP move to the cytoplasm?
Adenine nucleotide translocase
What do LHON, MERRF, and MELAS have in common?
All the result of defects to the mitochondrial genome.
What is Mutarotation?
Conversion of a-Glucose(lowest energy) to b-glucose
What is a danger of sugars in linear form?
They have reducing power - can be measured in urine
Bind HbA1C(early glycation product)
More oxidative stress results in Advanced Glycation End-product
How is glucose activated?
Glucose-1-phosphate + UTP ->UDP-Glucose Pyrophosphorylase -> UDP-Glucose + PPi
Describe the process of breaking down polysaccharides.
a-amylase in saliva(then more so in small intestine) makes random cuts -> oligosaccharidase, alpha-glucosidase, isomaltase, lactase, sucrase, and maltase.
Where are hexokinase and glucokinase found? What is the difference?
Hexokinase - everywhere not the liver, inhibited by product
Glucokinase - found in liver, not inhibited by product
What is fasting hypoglcemia?
Deficiency of Fructose-1,6-bisphosphatase activity
-Ergo no gluconeogenesis
Is glycolysis aerobic or anaerobic?
What is a common side effect of Traditional Chinese Medicine?
Arsenic poisoning - no ATP from phosphoglycerate kinase step in glycolysis. It subs in for the phosphate during previous step and dissociates right away.
What is the committed step in Glycolysis?
Fructose-1-phosphate to fructose-1,6-bisphosphate
How is fructose processed?
Mainly in liver
fructose 1 phosphate -> aldolase B->glyceraldehyde(needs phosphorylation) and dihydroxyacetone phosphate ->glycolysis
Describe the degradation of Galactose.
galactose->galactokinase->galactose 1-phosphate->galactose 1-phosphate uridyl transferase->UDP-galactose->UDPG 4-epimerase-> UDP-glucose -> glucose 1-phsphateuridyltransferase -> glucose 1-phosphate
What is Essential fructosuria?
No fructokinase -> no uptake -> benign
What is hereditary fructose intolerance?
Deficiency in aldolase B, therefore fructose-P accumulates in liver.
What are the 3 types of Galactosemia?
Galactose-1 phosphate uridyl transferase deficiency(classic and severe)
Galactokinase deficiency (no fixation in cells)
UDP-galactose epimerase deficiency
How is hexokinase regulated?
Inhibited by Glucose-6-phosphate, Acetyl-CoA, Glucagon
What is the main regulation step of Glycolysis and how is it regulated?
Inhibited by ATP and citrate
Stimulated by hormones, ADP, AMP
What is the role of fructose 2,6-bisphosphate in glycolysis?
How do the Muscle and Brain transport NADH vs the Liver and Heart?
Transport into the mitochondria
Muscle and Brain -> Glycerol phosphate shuttle
Heart and Liver -> Malate-aspartate shuttle
Describe the Glycerol Phosphate Shuttle.
glycerol 3 phosphate->glycerol 3 phosphate dehydrogenase +FADH in mitochondria -> dihydroxyacetone phosphate out
Describe the Malate-aspartate shuttle.
Aspartate in cytosol ->Oxaloacetate ->Malate and NAD ->into mitochondria -> malate->Oxaloacetate and NADH -> aspartate in mitochondria
Lactic Acid Fermentation
Pyruvate->lactate dehydrogenase->lactate + NAD
Opposite occurs in the liver.
More energy to make it go other way, though.
How is glucose taken up from the diet?
secondary active transport with NA+
What are the B-vitamins involved in the citric acid cycle and PDH complex?
B1 - Thiamine -TTP
B2 - Riboflavin -FAD
B3 - Niacin -NAD
B5 - Pantothenic Acid -CoA
B7 - Biotin -CO2 transfer
What is the difference between Ketosis and Ketoacidosis? What are some causes of each?
Ketosis is increased production of ketone bodies
-e.g. starvation or low carb diets
Ketoacidosis is when ketone levels lower pH
-e.g. Type 1 Diabetes
Go through glycolysis, all of it.
Glucose->Hexokinase->G 6-P->Glucose phosphate isomerase->F 6-P ->**Phosphofructokinase I**->F 1,6-BP->Fructose bisphosphate aldolase -> DHAP and Glyceraldehyde 3-P-> Triose P-isomerase->2 x G 3-P -> glyceraldehyde phosphate dehydrogenase +P(Aresenate sneaks in here) +NAD ->1,3 BPGlycerate -> Phosphoglycerate kinase-> 3-phosphoglycerate +ATP ->phosphoglyceromutase-> 2-Phosphoglycerate->Enolase->Phosphoenolpyruvate->Pyruvate kinase->Pyruvate + ATP**Committed Step
What are the GLUTs and where are they found?
Glut1 and Glut3 - basal glucose uptake in all tissues
Glut2 - liver, intestine, b-cells of pancreas
Glut4 - Muscle and adipose induced by insulin
Glut5 - small intestine fructose uptake
How is galactose processed?
Galactose-> Galactokinase-> Galactose 1-phosphate-> galactose 1-phosphate uridyltransferase-> UDP-Galactose-> UDPG-epimerase-> UDP-Glucose-> Glucose 1-phosphate uridyltransferase->Glucose 1 phosphate<->Glucose 6 phosphate
What are the glycogen storage disease?
Type I - Van Gierke - defective Glucose 6-phosphatase
Type II - Pompe - accumulation of glycogen in lysosome
Type III - Cori - defective glycogen debranching enzyme
Type V - McArdle disease - defect in muscle glycogen phosphorylase
Type VI - Same as V except in liver
How do you get fatty liver?
Ethanol-> alcohol dehydrogenase-> acetaldehyde-> aldehyde dehydrogenase-> Acetate-> Thiokinase-> Acetyl-CoA-> Fatty Acid Biosynthesis (CAC inhibited by NADH produced)
How is hormone-sensitive TAG lipase activated?
Epinephrine(glucagon) stimulates adenylate cyclase-> cAMP-> Protein kinase A-> Lipase-P(active)
What is carnitine's role?
To transfer long-chain fatty acids across the inner mitochondrial membrane. Carntine + fatty acyl-CoA-> Carnitine-acyl transferase I(CAT I)-> fatty-acyl carnitine + CoASH-> Carnitine translocase-> CAT II in mito. matrix-> fatty acyl-CoA + carnitine
Fatty acyl-CoA-> acyl-CoA dehydrogenase(FAD) 2nd and 3rd carbon atoms-> hydratase-> L-b-hydroxyacl-CoA-> b-hydroxyacl-CoA dehydrogenase(NAD)-> Thiolase-> shorter fatty acyl-CoA + acetyl-CoA.
What's different in the oxidation of saturated fatty acids and mono- or polyunsaturated ones?
Mono-unsaturated generally have a cis-double bond that needs isomerase to change to trans.
Poly-unsaturated generates conjugate double bonds(inhibit hydratase) that need 2,4 enoyl reductase to reduce them to a single cis-double bond, then isomerase to make it trans.
What's the role of peroxisomes in fatty acid oxidation?
Very long chain fatty acids(>24) are processed in similar manner without production of ATP down to 8 carbon fatty acid
How are ketone bodies formed?
Acetyl-CoA-(acetyl-CoA)> thiolase-> Acetoacetyl-CoA-(acetyl-CoA)> HMG-CoA synthase-> HMG-CoA-> HMG-CoA lyase-> acetoacetate-> acetone or b-hydroxybutyrate
How are ketone bodies used?
Hydroxbutyrate-(NAD)> Acetoacetate-(succinyl-S-CoA)>Acetoacetyl-CoA-> Thiolase-> 2 x Acetyl-CoA
Are fatty acids gluconeogenic?
If they have an even number of carbons-> NO
If they have an odd number of carbons-> YES(proprionic acid->succinyl-CoA)
Fatty Acid Biosynthesis
Acetyl-CoA-> **acetyl-CoA carboxylase**-> malonyl-CoA->pantothenic part of B-site
Acetyl-CoA->Acetyl on C-site -> Acetyl(C-Site) condensed to malonyl-CoA unit-> C-site open-> Reduction of carbonyl group->dehydration-> reduction of double bond-> transfer from B-site to C site and start over.
When does fatty acid biosynthesis end?
When the acid is 16 carbons long-> thioesterase cleaves it.
Can be elongated at cytoplasmic surface of ER
What kind of fatty acids can our body make(saturated vs unsaturated)?
It can make both, but it can only add a double bond up to carbon 10.
What is acetyl-CoA carboxylase and how is acetyl-CoA carboxylase regulated?
It catalyzes the committed step of fatty acid synthesis creating malonyl-CoA.
Stimulated by citrate(allosteric)
Inhibited by palmityl-CoA(product of fatty acid synth)(allosteric)
Where does biosynthesis take place?
Adipose tissues, liver, and intestines
How do you make a glycerol-3-phosphate?
Phosphorylate glycol from frutcose or breakdown of glycerolipids via glycerol kinase (everywhere except muscle and adipose)
Reduce DHAP via glycerol-3-phosphate dehydrogenase and NADH (in muscle/adipose)
How do you make a triacylglycerol?
"activate" fatty acids to fatty acyl-CoA
Glycerol-3-phosphate+fatty acyl-CoA-> acyltransferase-> lysophosphatidic acid-(fatty acyl-CoA)> acyl transferase-> phosphatide-> Phosphatidate phosphohydrolase->DAG-(Acyl-CoA)>DAG acyl transferase->TAG
OR 2-monoacylglycerol-(Acyl-CoA)> monoacylglycerol acyl transferase(intestine)->DAG then the same.
What are chylomicrons?
Chylomicrons start in enterocytes where TAGs are packaged in them, then they are carried in the lymph/blood until lipoprotein lyases in walls of capillaries release the TAGS.
What are the four major glycerophospholipids?
What nucleotide is used in biosynthesis of glycerophospholipids?
Describe the glycerophospholipid biosynthetic pathway using PA as an intermediate.
Phosphatidate + CTP-> CTP-phosphatidate cytidyl transferase-> CDP-diacylglycerol-(inositol)> phosphatidyl inositol
Describe the biosynthetic pathway of PC and PE.
Ethanolamine(or choline) + ATP-> phosphoethanolamine(phosphocholine)-> P-ethanolamine(P-choline)-(CTP)> CDP-ethanolamine(CDP-choline)-(DAG)> PE(PC) + CMP
What is the alternate route between PE and PC?
The nitrogen of PE can be methylated to PC
How do you make PS?
PE + serine-> PS + ethanolamine
What are the different phospholipase categories?
A1- acyl group from C-1
A2- acyl group from C-2
B- acyl group from C-1 or C-2 from lysophospholipids
C- phosphoryl head-group
D- non-phosphorylated head-group
What is a sphingolipid?
DOES NOT HAVE GLYCEROL
Has sphingosine amide linked long chain fatty acid
Precursor is Ceramide
How do you make sphingomyelin?
PC + ceramide<-> DAG + sphyingomyelin
What are the three main categories of phospholipids?
Cerebroside-monosaccharide attached to ceramide
Globosides- oligosaccharide, 2-4 sugar residues, no charge
Gangliosides- oligosaccharide, negative charge from carboxyl of sialic acid
What are the 2 kinds of sphingolipids?
Phosphosphingolipids or glycolipids
Where are sphingolipids degraded and why is this an issue?
Lysosome. Only an issue if there is deficiency of degradative enzyme.(autosomal recessive)
What are the eicosanoids?
Derivatives of C-20 polyunsaturated fatty acids, hormones that affect cell in which they are produced or locally. Very short lives. Produced by all cells except RBC.
Prostanoids - prostaglandins and thromboxanes
What is the cyclooxygenase pathway and what does it make?
In ER, arachidonic acid-> prostaglandin synthase-> prostaglandin H-> Other prostaglandins and thromboxanes
What are the two enzymes in prostaglandin synthase?
Cyclooxygenase-> form intra-molecular cyclopentane ring, incorporate 2 molecules of oxygen to acyl chain
Hydroperoxidase-> reduces peroxide to hydroxyl
What are the two forms of COX?
COX-1 -> constitutive
COX-2 -> inducible in response to inflammation
Describe the lipoxygenase pathway of leukotriene biosynthesis.
Lipooxygenase incorporates single oxygen molecule into arachidonic acid creating endoperoxide and no ring formation
What are the two therapeutic methods of inhibiting eicosanoids?
NSAIDs - non-steroidal anti-inflammatory drugs - inhibit cyclooxygenase (no PG or TX)
Anti-inflammatory corticosteroids - inhibit phospholipase A2 (no leukotriene, TX, or PG)
Describe some characteristics of cholesterol.
Make 50% of our own
How do you make cholesterol?
2 x acetyl-CoA-> Thiolase-> acetoacyl-CoA-(acetyl-CoA)>HMG-CoA synthase-> HMG-CoA-(2NADPH)> **HMG-CoA reductase**-> mevalonate-(3ATP)> isoprene-(2 more isoprene)> farnesyl-(farnesyl)> squalene-> cholesterol
What are the derivatives of cholesterol?
Bile acids generally impact the 8C side chain.
Cholate and Deoxycholate for example
Needed to digest.
What is steatorrhea?
Failure to make enough bile acid leads to fatty stool
Is bile acid release into small intestine a reasonable way of getting rid of cholesterol?
NO. 95% reabsorbed.
What is cholelithiasis?
Precipitation of cholesterol withing the gallbladder resulting in gallstones.
Treat with Chenodiol - but hepatotoxic side effects.
How do you make a steroid hormone?
Made from 27C cholesterol to 21C or fewer.
Glucocorticoids, sex hormones
Ring structure remains, but modified with carbonyl, hydroxyl, double bonds.
How do you make Vitamin D?
7-dehydrocholesterol-> UV light->cholecalciferol-> calcitriol
How do TAGs, Cholesterol, and cholesteryl esters get around?
Chylomicrons, VLDL, IDL, LDL, HDL
What is the principle role of chylomicrons?
Delivery of dietary lipids to tissues(primarily TAGs)
What is the primary role of VLDLs?
Delivery of fatty acids to extrahepatic tissues.
What is the primary role of IDLs?
Migrate to liver and bind to hepatic lipase then bind to LDL receptor and endocytosis, or digestion to LDL by hepatic lipase.
What are the primary roles of LDL?
Delivery of cholesterol and cholesteryl esters from liver to tissues and organs including back to the liver.
What is the primary role of HDL?
Carry cholesterol from tissues back to the liver.
How does an HDL maintain the surface gradient of low cholesterol?
Lecihin Cholesterol Acyl Transferase rapidly converts cholesterol to cholesteryl esters
What do the following three enzymes do; lipoprotein lipase, hepatic lipase, lecithin cholesterol acyl transferase?
LPL- hydrolyze TAGs to fatty acids and glycerol in capillary walls of adipose and muscle
HL- hydrolyze TAGs in IDLs, convert IDLs to LDLs, also hydrolyze TAGs from chylomicrons
LCAT- mainly bound to HDL, catalyze transfer of fatty acids from lecithin(PC) in HDL monolayer to cholesterol to form cholesteryl ester.
What cells have Apo B-100?
VLDL, IDL, LDL
Binds LDL receptor
What cells have Apo B-48?
Structural role only
What cells have Apo C-II?
chylomicrons, VLDL, IDL, HDL*
Activates lipoprotein lipase
*only a reservoir/not active
What cells have Apo E?
Chylomicrons, VLDL, IDL, HDL*
Binds to LDL receptor
*Reservoir only/not active
What is atherosclerosis and how would you treat it?
buildup of deposits in the blood vessels consisting of cholesterol and debris.
-dietary restriction of cholesterol
-statin drugs(HMG-CoA reductase inhibitor)
-niacin administration(inhibits VLDL synthesis)
-bile acid sequestrant
-cholesterol absorption inhibitor
What is familial hypercholesterolemia?
High levels of LDL due to deficiency of functional LDL receptors.