Biochemistry - Metabolism

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Biochemistry - Metabolism
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  1. Metabolism Sites
    • Mitochondria
    • 1. Fatty Acid Oxidation (β-oxidation)
    • 2. Acteyl-CoA production
    • 3. TCA cycle
    • 4. Oxidative Phosphorylation

    • Cytoplasm
    • 1. Glycolysis
    • 2. Fatty Acid Synthesis
    • 3. HMP shunt
    • 4. Protein Synthesis (RER)
    • 5. Steroid Synthesis (SER)
    • 6. Cholesterol Synthesis

    • Both
    • 1. Heme Synthesis
    • 2. Urea Cycle
    • 3. Gluconeogenesis

    "HUGs take two (ie both)"
  2. Kinase
    Uses ATP to add high-energy phosphate group onto substrate

    eg: phosphofructokinase
  3. Phosphorylase
    Adds inorganic phosphate onto substrate without using ATP

    eg: glycogen phosphorylase
  4. Phosphatase
    Removes phosphate group from substrate

    eg: fructose 1,6 bisphosphatase
  5. Dehydrogenase
    Catalyzes oxidation-reduction reactions

    eg: pyruvate dehydrogenase
  6. Carboxylase
    Transfers CO2 groups with the help of biotin

    eg: pyruvate carboxylase
  7. Rate Determining Enzymes of Metabolic Processes
    • Glycolysis:
    • -Phosphofructokinase 1 (PFK1)
    • -⊕ Regulators: AMP, F2,6BP
    • -⊖ Regulators: ATP, citrate

    • Gluconeogenesis:
    • -Fructose-1,6-bisphosphonate
    • -⊕ Regulators: ATP
    • -⊖ Regulators: AMP, Fructose-2,6-BP

    • TCA Cycle
    • -Isocitrate dehydrogenase
    • -⊕ Regulators: ADP
    • -⊖ Regulators: ATP, NADH

    • Glycogen Synthesis
    • -Glycogen synthase
    • -⊕ Regulators: glucose, insulin
    • -⊖ Regulators: epinephrine, glucagon

    • Glycogenolysis
    • -Glycogen phosphorylase
    • -⊕ Regulators: AMP, epinephrine, glucagon
    • -⊖ Regulators: insulin, ATP

    • HMP Shunt
    • -Glucose-6-phosphate dehydrogenase (G6PD)
    • -⊕ Regulators: NADP+
    • -⊖ Regulators: NADPH

    • De novo pyrimidine synthesis
    • -Carbamoyl Phosphate synthetase II

    • De novo purine synthesis
    • -Glutamine-PRPP amidotransferase
    • -⊖ Regulators: AMP, IMP, GMP

    • Urea Cycle
    • -Carbamoyl phosphate synthetase I
    • -⊕ Regulators: N-acetylglutamate

    • Fatty Acid Synthesis
    • -Acetyl-CoA Carboxylase (ACC)
    • -⊕ Regulators: insulin, citrate
    • -⊖ Regulators: glucagon, palmitoyl-CoA

    • Fatty Acid Oxidation
    • -Carnitine acyltransferase I
    • -⊖ Regulators: Malonyl-CoA

    • Ketogenesis
    • -HMG-CoA Synthase

    • Cholesterol Synthesis
    • -HMG-CoA Reductase
    • -⊕ Regulators: Insulin, thyroxine
    • -⊖ Regulators: glucagon, cholesterol
  8. Summary of Pathways
  9. ATP Synthesis
    • Aerobic Metabolism (32 ATP)
    • 1. Malate-Aspartate Shuttle (heart and liver) → 2 ATP
    • 2. Glycerol-3-phosphate shuttle (muscle) → 30 ATP

    Anaerobic Glycolysis (2 ATP/glucose molecule)

    **ATP hydrolysis can be coupled to energetically unfavorable reactions

  10. Activated Carriers
  11. Universal Electron Acceptors
    • Nicotinamides:
    • -NAD+ (from Vitamin B3)
    • -NADP+

    NAD+ usually used in catabolic processes to carry reducing equivalents away as NADH

    NADPH is used in anabolic processes (steroids and FA synthesis) as a supply of reducing equivalents

    • NADPH is a product of the HMP shunt, used in:
    • -anabolic processes
    • -respiratory burst
    • -P-450
    • -glutatione reductase

    • Flavin Nucleotides:
    • -FAD+ (from Vitamin B2)
  12. Carbohydrate Metabolism
    Digested in mouth and intestine and absorbed in small intestine

    • Cleavage into monosaccharides
    • -Starch (polysaccharide): hydrolyzed by α amylase in saliva and pancreatic secretions
    • -Disaccharides and Oligosaccharides hydrolyzed by brush border enzymes on intestinal epithelial cells
    • -monosaccharides: glucose, galactose, fructose

    • Monosaccharides are absorbed by carrier-mediated transport (GLUT transporters)
    • -travel to liver via portal vein

    • Pathways:
    • 1. Oxidation to CO2 and H2O for energy (glycolysis/lactic acid synthesis, TCA, ETC)
    • 2. Storage as glycogen
    • 3. Conversion to triglycerides
    • 4. Release into general circulation
  13. Hexokinase vs Glucokinase
    Phosphorylation of glucose to glucose-6-phosphate is the first step of glycolysis (and first step of glycogen synthesis in the liver)

    Reaction is catalyzed by either hexokinase or glucokinase depending on the tissue!

    Phosphorylation traps glucose inside a cell

    • Hexokinase:
    • -ubiquitous
    • -high affinity (low Km)
    • -low capacity (low Vmax)
    • -uninduced by insulin
    • -feedback inhibited by G6P

    • Glucokinase:
    • -Liver and β cells of pancreas
    • -low affinity (high Km)
    • -high capacity (high Vmax)
    • -induced by insulin


    • Low glucose concentrations:
    • -hexokinase sequesters glucose in tissue

    • High glucose concentrations:
    • -excess glucose stored in the liver

    "glucokinase is a glutton. It has a high Vmax because it cannot be satisfied"
  14. Glycolysis
    • Location:
    • -cytoplasm

    • Net Equation:

    **Equation not balanced chemically, and exact balanced equation depends on ionization state of reactants and products

    • Steps that require ATP:
    • 1. Glucose → Glucose-6-P
    • -glucokinase(liver)/hexokinase(tissues)
    • -⊖ Regulators: G6P hexokinase, F6P glucokinase

    • 2. Fructose-6-P → Fructose-1,6-BP
    • -Phosphofructokinase-1 (RATE LIMITING STEP)
    • -⊕ Regulators: AMP, F-2,6-BP
    • -⊖ Regulators: ATP, citrate

    • Steps that produce ATP:
    • 1. 1,3-BPG ⇌ 3-PG
    • -Phosphoglycerate kinase

    • 2. phosphoenolpyruvate → pyruvate
    • -Pyruvate kinase
    • -⊕ Regulators: F-1,6-BP
    • -⊖ Regulators: ATP, alanine
  15. NADH generated from Glycolysis
    -Glycerol Phosphate Shuttle
    -Malate-Aspartate Shuttle
    -does NOT pass directly through mitochondrial inner membrane to participate in ETC and oxidative phosphorylation

    • Glycerol Phosphate Shuttle
    • -most tissues
    • -transfers electrons from cytosolic NADH to mitochondrial FADH2
    • -generates 2 (FA: 1.5) ATP

    • Malate-Aspartate Shuttle
    • -heart, muscle, liver
    • -transfers electrons to mitochondrial NADH
    • -generates 3 (FA: 2.5) ATP
  16. Glycolysis: Regulation by F2,6BP



    FBPase-2 and PFK2 are part of the same complex (enzyme) but respond in opposite manners to phosphorylation by protein kinase A (PKA)

    • FBPase-2 catalyzes F2,6BP → F6P
    • -active in fasting state
    • -less glycolysis
    • -more gluconeogenesis

    • PFK-2 catalyzes F6P → F2,6BP
    • -active in fed state
    • -more glycolysis
    • -less gluconeogenesis

    • Fasting State:
    • ↑ glucagon → ↑ cAMP → ↑ PKA → ↑ FBP-ase2/↓
    •  PFK2 → LESS GLYCOLYSIS

    • Fed State:
    • ↑ insulin → ↓ cAMP → ↓ PKA → ↓ FBPase2/↑ PFK2 → MORE GLYCOLYSIS
  17. Pyruvate Dehydrogenase Complex
    pyruvate + NAD+ + CoA → acetyl-CoA + CO2 + NADH

    • Complex contains 3 enzymes that require 5 cofactors:
    • 1. Pyrophosphate (B1, thiamine; TPP)
    • 2. FAD (B2, riboflavin)
    • 3. NAD (B3, niacin)
    • 4. CoA (B5, pantothenate)
    • 5. Lipoic Acid

    • Activated by exercise:
    • -↑ NAD+/NADH ratio
    • -↑ ADP
    • -↑ Ca2+

    Pyruvate dehydrogenase complex is similar to the α-ketoglutarate dehydrogenase complex (same cofactors, similar substrate and action), which converts α-ketoglutarate to succinyl-CoA (TCA cycle)

    • **Arsenic inhibits lipoic acid
    • -vomiting
    • -rice water stools
    • -garlic breath
  18. Pyruvate Dehydrogenase Complex Deficiency
    • Causes:
    • -most cases due to mutations in X-linked gene for E1-α subunit of PDC

    • Pathophysiology:
    • -causes backup of substrate (pyruvate and alanine)
    • -results in lactic acidosis (excess pyruvate → anaerobic metabolism)

    • Findings:
    • -neurologic defects
    • -usually starts in infancy

    • Treatment:
    • -↑ intake of ketogenic nutrients (high fat content or ↑ lysine and leucine)

    Lysine and Leucine: the onLy pureLy ketogenic amino acids
  19. Pyruvate Metabolism
    • 1. Alanine aminotransferase (ALT)
    • -Cofactors: B6
    • -alanine carries amino groups from the muscle to the liver
    • -Cahill cycle
    • -occurs in cytosol

    • 2. Pyruvate Carboxylase:
    • -Cofactors: biotin
    • -oxaloacetate can replenish TCA cycle or be used in gluconeogenesis
    • -occurs in mitochondria

    • 3. Pyruvate dehydrogenase
    • -Cofactors: B1, B2, B3, B5, Lipoic acid
    • -transition from glycolysis to the TCA cycle
    • -converts pyruvate to acetyl-CoA
    • -occurs in the mitochondria

    • 4. Lactic acid dehydrogenase
    • -Cofactor: B3
    • -end of anaerobic glycolysis
    • -Cori cycle
    • -major pathway in RBCs, leukocytes, kidney medulla, lens, testes and cornea

  20. TCA Cycle (Krebs Cycle)


    • Acetyl CoA
    • -produced by the catabolism of carbohydrates, fats and proteins

    • Produces per Acetyl-CoA:
    • -3 NADH
    • -1 FADH2
    • -2 CO2
    • -1 GTP
    • = 10 ATP

    • ** uses different calculation (some = 12 ATP)!
    • -NADH = 2.5 ATP (3)
    • -FADH2 = 1.5 ATP (2)
    • -GTP = ATP

    ***2 pyruvates generated/glucose (20 ATP/24 ATP)

    Occurs in the Mitochondria

    • α-ketoglutarate dehydrogenase complex
    • -requires the same cofactors as PDH complex  (B1, B2, B3, B5, lipoic acid)

    "Citrate Is Krebs' Starting Substrate For Making Oxaloacetate"

    Citrate → Isocitrate → α-Ketoglutarate → Succinyl-CoA → Succinate → Fumarate → Malate → Oxaloacetate
  21. Electron Transport Chain and Oxidative Phosphorylation
    • NADH:
    • -electrons from glycolysis enter mitochondria via the malate-aspartate or glycerol 3-phosphate shuttle

    • FADH2:
    • -electrons are transferred to complex II (at a lower energy level than NADH)
    • -bypass complex I

    The passage of electrons results in the formation of a proton gradient that drives the production of ATP



    • 1 NADH = 3 ATP
    • 1 FADH2 = 2 ATP
  22. Oxidative Phosphorylation Poisons
    • 1. Electron Transport inhibitors
    • 2. ATP Synthase Inhibitors
    • 3. Uncoupling Agents
  23. Electron Transport Inhibitors
    • Rotenone
    • Cyanide
    • Antimycin A
    • CO

    • Mechanism:
    • -directly inhibit electron transport
    • -causes a ↓ proton gradient and blocks ATP synthesis
  24. ATP Synthase Inhibitors
    Oligomycin

    • Mechanism:
    • -directly inhibits mitochondrial ATP synthase
    • -increases proton gradient
    • -no ATP produced b/c electron transport stops
  25. Uncoupling Agents
    • 2,4 DNP
    • Aspirin (fevers often occur after aspirin OD)
    • Thermogenin (UCP) in brown fat

    • Mechanism:
    • -increase permeability of membrane
    • -causes a decreased proton gradient and increased O2 consumption
    • -ATP synthesis stops but electron transport continues
    • -produces heat
  26. Gluconeogenesis
    • -occurs mainly in the liver and kidney

    -synthesis of glucose from small noncarbohydrate precursor (such as lactate and alanine

    • -involves the reversible reactions of glycolysis
    • -separate steps to bypass the non-reversible steps of glycolysis
  27. Gluconeogenesis: Irreversible Enzymes
    Pathway Produces Fresh Glucose

    • Pyruvate Carboxylase
    • -in mitochondria
    • -pyruvate → oxaloacetate
    • -requires biotin, ATP
    • -activated by acetyl CoA

    • PEP Carboxykinase
    • -in cytosol
    • -oxaloacetate → PEP
    • -require GTP

    • Fructose-1,6-bisphosphatase
    • -in cytosol
    • -F1,6BP → F6P

    • Glucose-6-phosphatase
    • -in ER-glucose6P → glucose
  28. Cori Cycle
    • Function:
    • -shuttling of gluconeogenic substrates between muscle and liver

    -lactate from exercising muscle carried by circulation to liver (substrate for gluconeogenesis)

    -liver releases synthesized glucose into circulation for transport back to the muscles
  29. HMP Shunt (Pentose Phosphate Pathway)
    • Products (from G6P):
    • 1. NADPH (needed for reductive reactions: glutatione reduction inside RBCs)
    • 2. Ribose (nucleotide synthesis)
    • 3. Glycolytic intermediates

    • Two Phases: oxidative and non-oxidative
    • -both occur in cytoplasm

    NO ATP used or produced

    • Sites:
    • -lactating mammary glands
    • -liver
    • -adrenal cortex
    • -RBCs

    • Oxidative Phase (irreversible)

    • Nonoxidative (Reversible)
  30. Respiratory Burst (Oxidative Burst)
    Activation of membrane-bound NADPH oxidase (Neutrophils, monocytes)

    Important role in immune response → rapid release of reactive oxygen intermediates

    NADPH plays a role in the creation of ROIs and in their neutralization



    • Chronic Granulomatous Disease:
    • -NADPH oxidase deficiency
    • -WBCs of patients with CGD can utilize H2O2 generated by invading organisms and convert it to ROIs
    • -patients are at an increased risk for infection by catalase-positive species (S. aureus, Aspergillus) because they neutralize their own H2O2
  31. Glucose-6-Phosphate Dehydrogenase Deficiency
    • Epidemiology:
    • -most common human enzyme deficiency
    • -more prevalent among blacks
    • -X-linked recessive

    • Pathophysiology:
    • -unable to regenerate NADPH (HMG shunt/PPP)
    • -NADPH is needed to keep glutathione reduced
    • -glutathione detoxifies free radicals and peroxides
    • -hemolytic anemia (poor RBC defense against oxidizing agents)

    • Triggers of Hemolysis
    • 1. Oxidizing Agents
    • -fava beans
    • -sulfonamides
    • -primaquine
    • -anti-TB meds

    • 2. Infection
    • -free radicals generated by inflammatory response diffuse into RBCs

    • Findings:
    • -Heinz bodies: oxidized Hemoglobin precipitated within RBCs
    • -Bite Cells: result from phagocytic removal of Heinz bodies by splenic MΦs

    "Bite into some Heinz Ketchup"

  32. Fructose Metabolism
    • Takes place in the liver

    ***Fructose metabolism bypasses the rate-limiting step of glycolysis (PFK) by this pathway

    • Major Enzymes:
    • -Fructokinase
    • -Aldolase B
  33. Disorders of Fructose Metabolism
    • 1. Essential Fructosuria
    • 2. Fructose Intolerance

    ** disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism
  34. Essential Fructosuria
    • Pathophysiology:
    • -defect in fructokinase
    • -autosomal recessive

    • Presentation:
    • -benign, asymptomatic condition
    • -fructose is not trapped in cells (not phosphorylated)

    • Findings:
    • -fructose in blood
    • -fructose in urine
  35. Fructose Intolerance
    • Pathophysiology:
    • -hereditary deficiency in aldolase B
    • -autosomal recessive
    • -F1P accumulates causing a decrease in available phosphate → inhibition of glycogenolysis and gluconeogenesis
    • -fructose metabolism takes place in the liver

    • Presentation:
    • -hypoglycemia
    • -jaundice
    • -cirrhosis
    • -vomiting

    • Treatment:
    • -decrease intake of fructose and sucrose (glucose + fructose)
  36. Galactose Metabolism
    • Eventual conversion to glucose-1-P
    • -enters glycolysis/gluconeogenesis pathways

    • Major Enzymes:
    • -Galatokinase
    • -Uridyl Transferase

    "Fructose is to Aldolase B as Galatose is to Uridyl Transferase (FAB GUT)"
  37. Disorders of Galactose Metabolism
    • 1. Galactokinase Deficiency
    • 2. Classic Galactosemia

    Disorders of galactose metabolism cause worse symptoms than analogous disorders of fructose metabolism
  38. Galactokinase Deficiency
    • Pathophysiology:
    • -hereditary galactokinase deficiency
    • -autosomal recessive
    • -galactitol accumulates if galactose is present in diet

    • Presentation:
    • -relatively mild condition
    • -galactose in blood and urine
    • -infantile cataracts
    • -may initially present as failure to tract objects or develop a social smile
  39. Classic Galactosemia
    • Pathophysiology:
    • -absence of galactose-1-phosphate uridyltransferase
    • -autosomal recessive
    • -damage caused by accumulation of toxic substances (galactitol → accumulates in lens of eye)

    • Symptoms:
    • -failure to thrive
    • -jaundice
    • -hepatomegaly
    • -infantile cataracts
    • -mental retardation

    • Treatment:
    • -exclude galactose and lactose (galactose + glucose) from diet

    ** the more serious defects lead to PO4 depletion
  40. Sorbitol


    • Alternative way to trap glucose in cells (other than phosphorylation):
    • -convert it to it's alcohol counterpart sorbitol by aldol reductase

    Some tissues then convert sorbitol to fructose using sorbitol dehydrogenase

    Tissues with an insufficient amount of sorbitol dehydrogenase are at risk for intracellular sorbitol accumulation → osmotic damage

    Schwann Cells, retina and kidneys have only aldose reductase

    • Leads to:
    • -cataracts, retinopathy and peripheral neuropathy in diabetics with chronic hyper glycemia
  41. Lactase Deficiency
    • Pathophysiology:
    • -age-dependent and/or hereditary
    • -more common in African Americans and Asians
    • -loss of brush border lactase
    • -may also follow gastroenteritis

    • Symptoms:
    • -bloating
    • -cramps
    • -osmotic diarrhea

    • Treatment:
    • -avoid dairy products
    • -add lactase pills to diet
  42. Amino Acids
    **Only L-form Amino acids are found in proteins

    • Essential Amino Acids:
    • -Glucogenic: Met, Val, His
    • -Glucogenic/Ketogenic: Ile, Phe, Thr, Trp
    • -Ketogenic: Leu, Lys
    • **need to be supplied in diet

    • Acidic Amino Acids:
    • -Asp and Glu
    • (negatively charged at body pH)

    • Basic Amino Acids:
    • -Arg (most basic)
    • -Lys
    • -His (no charge at body pH)
    • **Arg and His are required during periods of growth
    • ***Arg and Lys are increased in histones (bind negatively charged DNA)
  43. Amino Acid Metabolism
    • Amino Acid breakdown provides:
    • 1. Nitrogen containing substances for synthesis of:
    • -nonessential AAs
    • -purines and pyrimidines
    • -porphyrins
    • -NTs
    • -hormones

    • 2. Carbon Skeletons
    • -oxidized in TCA for energy
    • -substrates for gluconeogenesis
    • -substrates for FA synthesis

    • Removal of Amino Acid Nitrogen
    • -deamination
    • -urea cycle detoxification of NH4+

    • Removal of Amino Acid Carbon Skeletons
    • -enter TCA
    • -ketogenic (enter through Acetyl CoA)
    • -glucogenic (enter through α-KG, Fumarate, OAA)
  44. Urea Cycle



    Amino Acid Catabolism results in the formation of common metabolites (eg: pyruvate, acetyl-CoA), which serve as metabolic fuels

    Excess nitrogen (NH4+) is converted to urea and excreted by the kidneys

    Urea cycle occurs in the liver

    • Important enzymes:
    • -Carbamoyl Phosphate Synthase I (rate limiting)
    • -Ornithine Transcarbamoylase

    • "Ordinarily, Careless Crappers Are Also Frivolous About Uriniation"
    • -Ornithine
    • -Carbamoyl Phosphate
    • -Citrulline
    • -Aspartate (donates NH4+)
    • -Argininosuccinate
    • -Fumarate
    • -Arginine
    • -Urea
  45. Transport of Ammonium by Alanine and Glutamate
    • The first half of this reaction in the muscle is showing the breakdown of amino acids by transamination. This results in glutamate and an α-ketoacid that can enter the TCA (ie: pyruvate)
    • The ammonium must then be transferred to the liver to be processed by the urea cycle.

    • Transamination:
    • -transfer of amino group from the AA (eg: alanine) to α-ketoglutarate resulting in an α-keto  (eg: pyruvate) glutamate
    • -amino groups of AAs are ultimately funneled to glutamate
    • -catalzyed by aminotransferases (ALT)

    • Transport of ammonia to the liver
    • 1. Glucose-Alanine Cycle
    • -glucose is converted to pyruvate (aerobic glycolysis)
    • -transamination of of pyruvate to form alanine
    • -alanine is transported by the blood to the liver

    • 2. Cori Cycle
    • -in the absence of oxygen (anaerobic glycolysis) pyruvate is converted to lactate
    • -lactate is transferred through the blood to the liver

    Once in the liver both alanine and lactate are reconverted to pyruvate, which is transaminated to glutamate, and the ammonia enters the urea cycle
  46. Hyperammonemia
    • Etiology:
    • -can be acquired (liver disease) or hereditary (urea cycle enzyme deficiencies

    • Pathophysiology:
    • -results in excess NH4+
    • -depletes α-ketoglutarate leading to inhibition of the TCA

    • Ammonia Intoxication Presentation:
    • -tremor
    • -asterixis
    • -slurring of speech
    • -somnolence
    • -vomiting
    • -cerebral edema
    • -blurring of vision

    • Treatment:
    • -limit protein in the diet
    • -benzoate or pheylbutyrate (both bind amino acid and lead to excretion)
    • -lactulose acidifies the GI tract and traps NH4+ for excretion
  47. Ornithine transcarbamoylase deficiency
    • Epidemiology:
    • -most common urea cycle disorder
    • -X-linked recessive (all other urea cycle enzyme deficiencies are autosomal recessive)

    • Pathophysiology:
    • -interferes with the body's ability to eliminate ammonia
    • -excess carbamoyl phosphate is converted to orotic acid (part of pyrimidine synthesis pathway)

    • Presentation:
    • -often evident the first days of life
    • -may present with late onset
    • -sx of hyperammonemia

    • Findings:
    • -elevated orotic acid in blood and urine
    • -decreased BUN
  48. Amino Acid Derivatives


    • Phenylalanine:
    • -Thyroxine
    • -Melanin
    • -DA
    • -NE
    • -Epi

    • Tryptophan:
    • -NAD+/NADP+
    • -Serotonin
    • -Melatonin
    • Histidine:
    • -histamine

    • Glycine:
    • -prophyrin → heme

    • Arginine:
    • -creatine
    • -urea
    • -nitric oxide

    • Glutamate:
    • -GABA
    • -Glutathione
  49. Catecholamine Synthesis/Tyrosine Catabolism
  50. Phenylketonuria
    • Epidemiology:
    • -autosomal recessive
    • -incidence = 1:10,000
    • -screen for 2-3 days after birth (normal at birth b/c of maternal enzyme during fetal life)

    • Pathophysiology:
    • -decreased phenylalanine hydroxylase (first step in tyrosine catabolism)
    • -OR decreased tetrahydrobiopterin (THB) cofactor (malignant phenylketonuria)
    • -tyrosine becomes essential
    • -elevated phenylalanine (excess phenylketones in urine)

    • Findings:
    • -mental retardation
    • -growth retardation
    • -seizures
    • -fair skin (can't produce melanin)
    • -eczema
    • -musty body odor

    "disorder of aromatic amino acid metabolism → musty body odor"

    • Treatment:
    • -decrease phenylalanine in diet (aspartame: NutraSweet)
    • -increase tyrosine in diet

    • Maternal PKU:
    • -lack of proper dietary therapy during pregnancy
    • -Findings in infant: microcephaly, mental retardation, growth retardation, congenital heart defects
  51. Alkaptonuria (ochronosis)
    • Pathophysiology:
    • -congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine to fumarate
    • -autosomal recessive
    • -benign!

    • Findings:
    • -dark connective tissue
    • -brown pigmented sclera
    • -urine turns black on prolonged exposure to air
    • -may have debilitating arthralgias (homogentisic acid is toxic to cartilage)
  52. Albinism
    • Congenital Deficiency of:
    • 1. Tyrosinase
    • -inability to synthesize melanin from tyrosine
    • -autosomal recessive

    • 2. Defective Tyrosine transporters
    • -decreased amounts of tyrosine and thus melanin

    • Pathophysiology:
    • -can result from a lack of migration of neural crest cells
    • -variable inheritance due to locus heterogeneity (vs ocular albinism: X-linked recessive)

    • Complications:
    • -lack of melanin → increase risk of skin cancer
  53. Homocystinuria
    • 3 forms (all autosomal recessive)
    • 1. Cystathionine synthase deficiency
    • -Treatment: ↓ Met, ↑ Cys, ↑ B12/folate in diet

    • 2. Decreased affinity of cystathione synthase for pyridoxal phosphate
    • -Treatment: ↑↑ vitamin B6 in diet

    • 3. Homocysteine methyltransferase deficiency
    • -requires B12

    • Pathophysiology:
    • -all forms result in excess homocysteine
    • -cysteine becomes essential

    • Findings:
    • -↑↑ homocysteine in urine
    • -mental retardation
    • -osteoporosis
    • -tall stature
    • -kyphosis
    • -lens subluxation (downward and inward)
    • -atherosclerosis (stroke and MI)

  54. Cystinuria
    • Epidemiology:
    • -common (1:7000)
    • -autosomal recessive

    • Pathophysiology:
    • -hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and arginine in the PCT of the kidneys
    • -excess cystine in the urine can lead to precipitation of hexagonal crystals and renal staghorn calculi
    • -cystine = 2 cysteines connected by disulfide bond

    • Treatment:
    • -good hydration
    • -urinary alkalinization
  55. Maple Syrup Urine Disease
    • Pathophysiology:
    • -autosomal recessive
    • -↓ α-ketoacid dehydrogenase (B1)
    • -blocked degradation of branched amino acids (Ile, Leu, Val)
    • -causes ↑ α-ketoacids in the blood (esp Leu)

    "I Love Vermont maple syrup, from maple trees (with branches)"

    • Presentation:
    • -severe CNS defects
    • -mental retardation
    • -death
    • -urine smells like maple syrup
  56. Hartnup Disease
    • Pathophysiology:
    • -autosomal recessive
    • -defective neutral amino acid transporter on renal and intestinal epithelial cells
    • -causes tryptophan excretion in urine and decreased absorption from the gut
    • -leads to pellagra!

    • Pellagra:
    • -niacin (B3) deficiency
    • -Dermatitis, dementia, diarrhea
  57. Glycogen Regulation by Insulin and Glucagon/Epinephrine


    • Glucagon (liver):
    • -maintain blood glucose by activation of hepatic glycogenolysis and gluconeogenesis
    • -stimulates production of cAMP → PKA
    • -PKA phosphoryates Glycogen phosphorylase kinase (active form)
    • -Glycogen phosphorylase kinase phosphorylates Glycogen phosphorylase (active)
    • -Glycogen phosphorylase → Glycogenolysis

    • Epinephrine (liver and muscle):
    • -also activates cAMP and PKA
    • -same effects as glucagon

    • Insulin:
    • -decrease glucose in blood
    • -dimerization of RTK
    • -activates protein phosphatase
    • -converts active form of glycogen phosphorylase kinase to inactive form (dephosphorylation)
    • -converts active form of glycogen phosphorylase to inactive form (dephosphorylation)
    • -decreases glycogenolysis

    • **Ca2+/Calmodulin in muscle
    • -activates phosphorylase kinase so that glycogenolysis is coordinated with muscle activty
  58. Glycogen
    • Structure:
    • -branches have α (1,6) bonds
    • -linkages have α (1,4) bonds

    • Skeletal Muscle:
    • -glycogen undergoes glycogenolysis: G1P → G6P
    • -G6P is rapidly metabolized during exercise

    • Hepatocytes:
    • -glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels

    • Glycogen Synthesis Important Enzymes:
    • -UDP-glucose phosphorylase
    • -Glycogen synthase
    • -Branching enzyme

    • Glycogenolysis Important Enzymes:
    • -Glycogen phosphorylase
    • -debranching enzymes

    **a small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase
  59. Glycogenolysis/Glycogen Synthesis
  60. Glycogen Storage Diseases
    • -12 types
    • -all result in abnormal glycogen metabolism and an accumulation of glycogen withing cells

    "Very Poor Carbohydrate Metabolism"

    • Types:
    • -Von Gierke's Disease (type I)
    • -Pompe's Disease (type II)-Cori's Disease (type III)
    • -McArdle's Disease (type V)
  61. Von Gierke's Disease
    • Deficient Enzyme:
    • -Glucose-6-Phosphatase
    • -autosomal recessive

    • Findings:
    • -severe fasting hypoglycemia
    • -↑↑ glycogen in liver
    • -↑ blood lactate
    • -hepatomegaly
  62. Pompe's Disease
    • Deficient Enzyme:
    • -Lysosomal α-1,4-glucosidase (acid maltase)
    • -autosomal recessive

    • Findings:
    • -cardiomegaly
    • -systemic findings
    • -leads to early death

    "Pompe's trashes the Pump (heart, liver, muscle)"
  63. Cori's Disease
    • Deficient Enzyme:
    • -debranching enzyme (α-1,6-glucosidase)
    • -autosomal recessive
    • **gluconeogenesis is intact

    • Findings:
    • -milder form of type I (Von Gierke's)
    • -normal blood lactate levels
  64. McArdle's Disease
    • Deficient Enzyme:
    • -skeletal muscle glycogen phosphorylase
    • -autosomal recessive

    • Findings:
    • -increase glycogen in muscle
    • -but cannot break it down → painful muscle cramps, myoglobinuria with strenuous exercise

    "McArdle's = Muscle"

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