USMLE (Fach) / Biochemistry - Metabolism (Lektion)

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• How is acetyl-CoA ultimately converted into fatty acids? What important cofactor is required to initiate this process? Acetyl-CoA → malonyl CoA (step requires biotin cofactor) → fatty acids
• How is acetyl-CoA ultimately converted into β-hydroxybutyrate? Acetyl-CoA → acetoacetyl-CoA → HMG-CoA → acetoacetate → β-hydroxybutyrate
• How is acetyl-CoA ultimately converted into cholesterol? Acetyl-CoA → acetoacetyl-CoA → HMG-CoA → mevalonate (via HMG-CoA reductase) → cholesterol
• Starting with acetyl-CoA, outline all of the steps within the TCA cycle. Acetyl CoA and oxaloacetate → citrate → isocitrate → α-ketoglutarate → succinyl-CoA → succinate → fumarate → malate → oxaloacetate
• Outline the steps in the conversion of pyruvate into phosphoenolpyruvate (PEP). Pyruvate → oxaloacetate via pyruvate carboxylase and oxaloacetate → phosphoenolpyruvate via PEP carboxykinase
• Fructose can enter glycolysis by 2 pathways. Outline them. Fructose → fructose-1-phosphate (via fructokinase) → either DHAP or glyceraldehyde → glyceraldehyde-3-P (both via aldolase B)
• Glucose-6-phosphate must undergo a reaction before export from the cell. What is the reaction? In what disease is this reaction impaired? Dephosphorylation via glucose-6-phosphatase into glucose; von Gierke disease
• Which 2 enzymes are responsible for ultimately converting galactose into glucose-1-phosphate? Galactose → galactose-1-phosphate via galactokinase; galactose-1-phosphate → glucose-1-phosphate via galactose-1-phosphate uridyltransferase
• Outline the steps by which glucose-6-phosphate may be converted into glycogen. Glucose-6-phosphate → glucose-1-phosphate → UDP-glucose → glycogen
• The 2 enzymes for converting galactose into glucose-1-phosphate may be impaired. What 2 diseases are these, and which is more severe? Galactokinase deficiency (1st step): mild galactosemia; galactose-1-phosphate uridyltransferase deficiency (2nd step): severe galactosemia
• The 2 enzymes for converting fructose into DHAP/glyceraldehyde may be impaired. What 2 diseases are these, and which is more severe? Fructokinase deficiency (1st step): essential fructosuria (mild); aldolase B (2nd step): fructose intolerance (severe)
• Triglyceride metabolism byproducts can ultimately reenter the glycolysis pathway. How does this happen? Triglyceride metabolism releases glycerol, which is converted into DHAP that becomes either glyceraldehyde-3-P or fructose-1,6-bisphosphate
• Argininosuccinate is converted into 2 different products in the urea cycle. What are they? What is each molecule's fate? Fumarate (enters the TCA cycle) and arginine (remains in the urea cycle)
• Starting with CO2 and NH3, outline all of the steps within the urea cycle. CO2 and NH3 → carbamoyl phosphate → citrulline (requires ornithine) → argininosuccinate → arginine (and fumarate) → ornithine (+ H2O → urea)
• ATP production Aerobic metabolism of glucose produces 32 net ATP via malate-aaspartate shuttle (heart and liver), 30 net ATP via glycerol-3-phosphate shuttle (muscle). Anaerobic glycolysis produces only 2 net ATP per glucose molecule (the NADH created needs oxygen to generate energy)
• Hexokinase vs glucokinase Phosphorylation of glucose to yield glucose-6-phosphate is catalyzed by glucokinase in the liver and hexokinase in other tissues. At low glucose concentrations, hexokinase sequesters glucose in the tissue.At high glucose concentrations, glucokinase helps to store glucose in the liver. Hexokinase:- Most tissues- Km lower (↑ affinity)- Vmax lower (↓ capacity)- Induced by insulin: no- Feedback-inhibited by glucose-6-phosphate: yes Glucokinase:- Liver, β cells of pancreas- Km higher (↓ affinity)- Vmax higher (↑ capacity)- Induced by insulin: yes- Feedback-inhibited by glucose-6-phosphate: no (by fructose-6-phosphate)- Gene mutation associated with maturity-onset-diabetes of the young (MODY)
• In glycolysis, which reactions generate ATP? Conversions of 1,3-bisphosphoglycerate to 3-phosphoglycerate and phosphoenolpyruvate to pyruvate
• Regulation by fructose-2,6-bisphosphate FBPase-2 (fructose bisphosphatase-2) and PFK-2 (phosphofructokinase-2) are the same bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A. Fasting state: ↑ glucagon → ↑ cAMP → ↑ protein kinase A → ↑ FBPase-2, ↓ PFK-2, less glycolysis, more gluconeogenesis Fed state: ↑ insulin → ↓ cAMP → ↓ protein kinase A → ↓ FBPase-2, ↑ PFK-2, more glycolysis, less gluconeogenesis
• Pyruvate dehydrogenase complex Mitochondrial enzyme complex linking glycolysis and TCA cycle. Pyruvate + NAD+ + CoA → Acetyl-CoA + CO2 + NADH Complex contains 3 enzymes that require 5 cofactors:1. Thiamine pyrophosphate (B1)2. Lipoic acid3. CoA (B5, pantothenic acid)4. FAD (B2, riboflavin)5. NAD (B3, niacin) - Activated by ↑ NAD+/NADH ratio, ↑ ADP, ↑ Ca2+- Similar to the α-ketoglutarate dehydrogenase complex, which converts α-ketoglutarate → succinyl-CoA.- Arsenic inhibits lipoic acid. Findings include pigmentary skin changes, skin cancer, vomiting and diarrhea, QT prolongation, garlic breath.
• Pyruvate metabolism 1. Alanine aminotransferase (B6): alanine carries amino groups to the liver from muscle 2. Pyruvate carboxylase (biotin): oxaloacetate can replenisch TCA cycle or be used in gluconeogenesis 3. Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid): transition from glycolysis to the TCA cycle 4. Lactic acid dehydrogenase (B3): end of anaerobic glycolysis
• TCA cycle (Krebs cycle) The TCA cycle produces 3 NADH, 1 FADH2, 2 CO2, 1 GTP per acetyl-CoA = 10 ATP/acetyl-CoA (2x everything per glucose) - Reactions occur in the mitochondria
• Electron transport chain and oxidative phosphorylation NADH electons from glycolysis enter mitochondria via the malate-aspartate or glycerol-3-phosphate shuttle. FADH2 electrons are transferred to complex II (succinate dehydrogenase). Electron transport inhibitors: Cause a ↓ proton gradient and block of ATP synthesis.- Rotenone: complex I (one) inhibitor- Antimycin A: complex III inhibitor- Cyanide (CN), carbon monoxide (CO), azide: complex IV inhibitors ATP synthase inhibitors: Directly inhibit mitochondrial ATP synthase, causing an ↑ protein gradient. No ATP is produced between electron transport stops.- Oligomycin Uncoupling agents: ↑ permeability of membrane, causing a ↓ proton gradient and ↑ O2 consumption. ATP synthesis stops, but electron transport continues. Produces heat.- 2,4-Dinitrophenol (used illicitly for weight loss)- Aspirin (fevers often occur after overdose)- Thermogenin in brown fat
• HMP shunt (pentose phosphate pathway) Provides a source of NADPH from abundanty available glucose-6-phosphate (NADPH is required for reductive reactions, eg, glutathione reduction inside RBCs, respiratory burst, the cytochrome P-450 system, fatty acid and cholesterol biosynthesis).Additionally, this pathway yields ribose for nucleotide synthesis and glycolytic intermediates.- No ATP is used or produced. Sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs.  2 distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm.- Oxidative (irreversible): Glucose-6-Pi → Ribulose-5-Pi- Nonoxidative (reversible): Ribulose-5-Pi ↔ Ribose-5-Pi + Glyceraldehyd-3-P, Fructose-6-P. Requires thiamine (B1).
• Glucose-6-phosphate dehydrogenase deficiency NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides. ↓ NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (eg, fava beans, sulfonamides, nitrofurantoin, primaquine/chloroquine, antituberculosis drugs). Infection can also precipitate hemolysis. - X-linked recessive disorder- Most common human enzyme deficiency- Most prevalent among African Americans, ↑ malarial resistance Heinz bodies = denatured hemoglobin precipitates within RBCs due to oxidative stressBite cells = result from the phagocytic removal of Heinz bodies by splenic macrophages
• Disorders of fructose metabolism Essential fructosuria: Defect in fructokinase.- Autosomal-recessive- Benign and asymptomatic, since fructose is not trapped in cells.- Hexokinase becomes 1° pathway for converting fructose to fructose-6-phosphate.- Fructose appears in blood and urine.- Can be detected by a copper reduction test, which nonspecifically detects the presence of reducing sugar. Hereditary fructose intolerance: Hereditary deficiency of aldolase B.- Autosomal-recessive- Fructose-1-phosphate accumulates, causing a ↓ in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis.- Symptoms present following consumption of fruit, juice, or honey.- Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in urine (copper reduction test)- Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.- Treatment: ↓ intake of both fructose and sucrose (glucose + fructose).
• Disorders of galactose metabolism Galactokinase deficiency: Hereditary deficiency of galactokinase.- Autosomal-recessive - Galactitol accumulates if galactose is present in diet.- Relatively mild condition.- Symptoms: galactose appears in blood (galactosemia) and urine (galactosuria); infantile cataracts. May present as failure to track objects or to develop a social smile. Classic galactosemia: Absence of galactose-1-phosphate uridyltransferase.- Autosomal-recessive- Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).- Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula).- Symptoms: failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can predispose to E coli sepsis in neonates.- Treatment: exclude galactose and lactose (galactose + glucose) from diet.
• Lactase deficiency Insufficient lactase enzyme → dietary lactose intolerance. Lactase functions on the intestinal brush boarder to digest lactose into glucose and galactose. - Primary: age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American descent.- Secondary: loss of brush border due to gastroenteritis, autoimmune disease, etc. - Congenital lactase deficiency: rare, due to defective gene - Stool demonstrates ↓ pH and breath shows ↑ hydrogen content with lactose hydrogen breath test.- Intestinal biopsy reveals normal mucosa. Findings: Bloating, cramps, flatulence, osmotic diarrhea Treatment: Avoid dairy products or add lactase pills to diet; lactose-free milk.
• Which are the 2 energy-requiring steps in the urea cycle? CO2 + NH3 to carbamoyl phosphate via carbamoyl phosphate synthetase I (2 ATP) and aspartate + citrulline to argininosuccinate (1 ATP)
• Hyperammonemia Can be acquired (eg, liver disease) or hereditary (eg, urea cycle enzyme deficiencies). - Presents with flapping tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision. - Excess NH3 depletes glutamate (GABA) in the CNS and α-ketoglutarate → inhibition of TCA cycle. Treatment: limit protein in diet.May be given to ↓ ammonia levels:- Lactulose to acidify the GI tract and trap NH4+ for excretion.- Antibiotics (eg, rifaximin, neomycin) to ↓ colonic ammoniagenic bacteria.- Benzoate, phenylacetate, or phenylbutyrate react with glycine or glutamine, forming products that are renally excreted.
• Ornithine transcarbamylase deficiency - Most common urea cycle disorder.- X-linked recessive (vs other urea cycle enzyme deficiencies, which are autosomal recessive). - Interferes with the body's ability to eliminate ammonia.- Often evident in the first few days of life, but may present later.- Excess carbamoyl phosphate is converted to orotic acid (as part of the pyrimidine synthesis pathway). Findings: - ↑ orotic acid in blood and urine- ↓ BUN- Symptoms of hyperammonemia- No megaloblastic anemia (vs orotic aciduria)
• Arginine derivatives? Arginine → Creatinine Arginine → Urea Arginine → Nitric oxide
• Phenylalanine derivatives Phenylalanine (+BH4) → Tyrosine (+BH4) → Dopa (+B6) → Dopamine (+Vitamin C) → Norepinephrine (+SAM) → Epinephrine Tyrosine → Thyroxine Dopa → Melanin
• Tryptophan derivatives Tryptophan → Niacin → NAD/NADH Tryptophan → Serotonin → Melatonin
• Catecholamine synthesis/catabolism Phenylalanine (+ BH4) → Tyrosine (+BH4) → Dopa (+ B6) → Dopamine (+ Vit. C) → Norepinephrine (+ SAM)→ Epinephrine Tyrosine → Homogentisic acid → Maleylacetoacetic acid → Fumarate → TCA cycle Dopa (Tyrosinase)→ Melanin Dopamine → Homovanillic acid Norepinephrine (COMT) → Normetanephrine → Vanillylmandelic acid Epinephrine → Metanephrine → Vanillylmandelic acid
• Phenylketonuria Due to ↓ phenylalanine hydroxylase or ↓ tetrahydrobiopterin (BH4) cofactor (malignant PKU).- Tyrosine becomes essential- Autosomal-recessive. Incidence ±1:10,000- Screening occurs 2-3 days after birth  ↑ phenylalanine → ↑ phenyl ketones in urine (phenylacetate, phenyllactate, phenylpyruvate) Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor Treatment: ↓ phenylalanine and ↑ tyrosine in diet, tetrahydrobiopterin supplementation- PKU patients must avoid the artificial sweetener aspartame, which contains phenylalanine - Maternal PKU – lack of proper dietary therapy during pregnancy. Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
• Maple syrup urine disease Blocked degradation of branched amino acids (isoleucine, leucine, valine) due to ↓ branched-chain α-ketoacid dehydrogenase (B1). - Autosomal recessive - Causes ↑ α-ketoacids in the blood, especially those of leucine - Causes severe CNS defects, intellectual disability, and death- Presentation: vomiting, poor feeding, urine smells like maple syrup/burnt sugar Treatment: restriction of isoleucine, leucine, valine in diet, and thiamine supplementation
• Alkaptonuria Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate → pigment-forming homogentisic acid accumulates in tissue- Autosomal recessive- Usually benign Findings:- Bluish-black connective tissue, ear cartialage, and sclerae (ochronosis)- Fair complexion- Urine turns black on prolonged exposure to air- May have debilitating arthralgias (homogentisic acid toxic to cartilage)
• Homocytinuria - Autosomal recessive Causes:- Cytathionine synthase deficiency (treatment: ↓ methionine, ↑ cysteine, ↑ B6, B12, and folate in diet)- ↓ Affinity of cystathionine synthase for pyridoxal phosphate (treatment: ↑↑ B6 and ↑ cysteine in diet)- Methionine synthase (homocysteine methyltransferase) deficiency (treatment: ↑ methionine in diet) All forms result in excess homocysteine.- ↑↑ homocysteine in urine, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), cardiovascular effects (thrombosis and atherosclerosis → stroke and MI), kyphosis, intellectual disability.
• Cystinuria Defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of cystine, ornithine, lysine and arginine.- Autosomal recessive. - Common (1:7000) - Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones.- Cystine is made of 2 cysteines connected by a disulfide bond. Diagnosis: Urinary cyanide-nitroprusside test Treatment: urinary alkalinization (eg, potassium citrate, acetazolamide) and chelating agents (eg, penicillamine) ↑ solubility of cystine stones; good hydration.
• Glycogen Branches have α-(1,6) bonds; linkages have α-(1,4) bonds. Skeletal muscle: Glycogen undergoes glycogenolysis → glucose-1-phosphate → glucose-6-phosphate Hepatocytes: Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels. Glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4 glucose residues remain on a branch. Then 4-α-D-glucanotransferase (debranching enzyme) moves 3 of the 4 glucose units from the branch to the linkage. Then α-1,6-glucosidase (debranching enzyme) cleaves off the last residue, liberating glucose. "Limit dextrin" refers to the one to four residues remaining on a branch after glycogen phosphorylase has already shortened it. A small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase (acid maltase).
• Lysosomal storage diseases - Sphingolipidoses Fabry disease (X-linked recessive)- Deficient enzyme: α-galactosidase A- Accumulated subsstrate: Ceramide trihexoside (globotriaosylceramide)- Presents during childhood or adolescence.- Early findings: Triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis- Late findings: Progressive renal failure, cardiovascular diseaseGaucher disease:- Deficient enzyme: β-glucocerebrosidase (β-glucosidase)- Accumulated substance: Glucocerebroside- Findings: Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone crises/fractures, Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)Niemann-Pick disease:- Deficient enzyme: Sphingomyelinase- Accumulated substance: Sphingomyelin ("No man picks his nose with his sphinger")- Findings: Progressive neurodegeneration, "cherry-red" spot on macula, hepatosplenomegaly, foam cells (lipid-laden macrophages). Early death.Tay-Sachs disease:- Deficient enzyme: Hexosaminidase A- Accumulated substance: GM2 ganglioside- Findings: Progressive neurodegeneration, developmental delay, hyperreflexia, hyperacusis, "cherry-red" spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs Niemann-Pick). Death usually <2 years.Krabbe disease:- Deficient enzyme: Galactocerebrosidase (galactosylceramidase)- Accumulated substance: Galactocerebroside, psychosine- Findings: Peripheral neuropathy, destruction of oligodendrocytes, developmental delay, optic atrophy, globoid cells Metachromatic leukodystrophy: - Deficient enzyme: Arylsulfatase A- Accumulated substance: Cerebroside sulfate- Findings: Central and peripheral demyelination with ataxia, dementia- Metachromasia: Enables a substance to shift the color spectrum such that the dys (eg, toluidine blue) will appear a different color (eg, reddish-pink) after application.
• Fatty acid metabolism Fatty acid synthesis requires transport of citrate from mitochondria to cytosol. Predominantly occurs in liver, lactating mammary glands, and adipose tissue.Citrate → citrate shuttle into cytoplasm –(ATP citrate lyase)→ Acetyl-CoA + CO2 → Malonyl-CoA → Palmitate Fatty chain degradation: Fatty acid + CoA –(Fatty Acyl-CoA synthetase)→ Fatty Acyl-CoA → Carnitine shuttle into mitochondria → β-oxidaiton (Acyl-CoA dehydrogenases)- Long-chain fatty acid (LCFA) degradation requires carnitine dependent transport into the mitochondrial matrix. Systemic 1° carnitine deficiency – inherited defect in transport of LCFAs into the mitochondria → toxic accumulation. Causes weakness, hypotonia and hypoketotic hypoglycemia.  Medium chain acyl-CoA dehydrogenase deficiency – ↓ ability to break down fatty acids into acetyl-CoA → accumulation of fatty acyl carnitines in the blood wth hypoketotic hypoglycemia. Causes vomiting, lethargy, seizures, coma, liver dysfunction, hyperammonemia. C8-C10 acyl carnitines in blood. Can lead to sudden death in infants or children. Treat by avoiding fasting, frequent feeding, high-carbohydrate, low-fat diet.
• Ketone bodies In the liver, fatty acids and amino acids are metabolized to acetoacetate and β-hydroxybutyrate (to be used in muscle and brain) In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate. Both processes cause a buildup of acetyl-CoA, which is shunted into ketone body synthesis. Ketone bodies: acetone, acetoacetate, β-hydroxybutyrate - Breath smells like acetone (fruity odor) - Urine test for ketones can detect acetoacetate, but not β-hydroxybutyrate - HMG-CoA lyase for ketone production- HMG-CoA reductase for cholesterol synthesis
• Apolipoproteins Apolipoprotein E:- Mediates remnant uptake by the liver- on chylomicron, chylomicron remnant, VLDL, IDL, HDL- not on LDL Apolipoprotein A-I:- Activates LCAT- on chylomicron, HDL Apolipoprotein C-II:- Lipoprotein lipase cofactor- on chylomicron, VLDL, HDL Apolipoprotein B-48:- Mediates chlyomicron secretion into lymphatics- on chylomicron, chylomicron remnant Apolipoprotein B-100:- Binds LDL receptor- on VLDL, IDL, LDL
• Familial dyslipidemias I - Hyperchylomicronemia- Autosomal-recessive- Lipoprotein lipase or apolipoprotein C-II deficiency- ↑ chylomicrons, TG, cholesterol- Pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no ↑ risk for atherosclerosis). Creamy layer in supernatant. II - Familial hypercholesterolemia- Autosomal-dominant- Absent or defective LDL receptors, or defective ApoB-100 receptors- IIa: LDL, cholesterol; IIb: LDL, cholesterol, VLDL- Heterozygotes (1:500) have cholesterol ≈300 mg/dL; homozygotes have cholesterol ≈700+ mg/dL. Accelerated atherosclerosis (MI before 20 years old), tendon xanthelomas, corneal arcus. III - Dysbetalipoproteinemia- Autosomal recessive- Defective ApoE- ↑ chylomicrons, VLDL- Premature atherosclerosis, tuberoeruptive and palmar xanthomas. IV - Hypertriglyceridemia- Autosomal-dominant- Hepatic overproduction of VLDL- ↑ VLDL, TG- Hypertriglyceridemia (>1000 mg/dL) can cause acute pancreatitis. Related to insulin resistance.
• Metabolism sites Mitochondria: Fatty acid oxidation (β-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis. Cytoplasm: Glycolysis, HMP shunt, and synthesis of steroids (SER), proteins (ribosomes, RER), fatty acids, cholesterol, and nucleotides. Both: Heme synthesis, urea cycle, gluconeogenesis.
• Rate-determining enzymes of metabolic process Glycolysis: Phosphofructokinase-1- AMP ⊕, fructose-2,6-biphosphate ⊕- ATP Θ, Citrate Θ Gluconeogenesis: Fructose-1,6-biphosphatase- Citrate ⊕- AMP Θ, fructose-2,6-biphosphate Θ TCA cycle: Isocitrate dehydrogenase- ADP ⊕- ATP Θ, NADH Θ Glycogenesis: Glycogen synthase- Glucose-6-phosphate ⊕, insulin ⊕, cortisol ⊕- Epinephrine Θ, glucagon Θ Glycogenolysis: Glycogen phosphorylase- Epinephrine ⊕, glucagon ⊕, AMP ⊕- Glucose-6-phosphate Θ, insulin Θ, ATP Θ HMP shunt: Glucose-6-phosphate dehydrogenase- NADP+ ⊕, NADPH Θ De novo pyrimidine synthesis: Carbamoyl phosphate synthetase II- ATP ⊕, PRPP ⊕- UTP Θ De novo purine synthesis: Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase- AMP Θ, inosine monophosphate (IMP) Θ, GMP Θ Urea cycle: Carbamoyl phosphate synthetase I- N-acetylglutamate ⊕ Fatty acid synthesis: Acetyl-CoA carboxylase (ACC)- Insulin ⊕, citrate ⊕- Glucagon Θ, palmitoyl-CoA Θ Fatty acid oxidation: Carnitine acyltransferase I- Malonyl-CoA Θ Ketogenesis: HMG-CoA synthase Cholesterol synthase: HMG-CoA reductase- Insulin ⊕, thyroxine ⊕- Glucagon Θ, cholesterol Θ
• Arsenic - Arsenic inhibits lipoic acid. Clinical findings: - Pigmentary skin changes- Skin cancer- Vomiting - Diarrhea containing blood- QT prolongation
• Pyruvate dehydrogenase complex deficiency Causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (ALT). - X-linked Findings:- Neurologic defects- Lactic acidosis- ↑ serum alanine starting in infancy Treatment: ↑ intake of ketogenic nutrients (eg, high fat content or ↑ lysine and leucine) → cannot be metabolized to pyruvate and consumption will not lead to increased production of lactic acid.
• Gluconeogenesis, irreversible enzymes Pyruvate carboxylase: In mitochondria. Pyruvate → oxaloacetate.- Requires biotin, ATP. Activated by acetyl-CoA. Phosphoenolpyruvate: In cytosol. Oxaloacetate → phosphoenolpyruvate.- Requires GTP. Fructose-1,6-biphosphatase: In cytosol. Fructose-1,6-biphosphate → fructose-6-phosphate.- Citrate ⊕, AMP ⊝, fructose-2,6-biphosphate ⊝. Glucose-6-phosphatase: In ER. Glucose-6-phosphate → glucose. - Enzymes found primarily in liver, kidney, interstitial epithelium.- Muscle cannot participiate in gluconeogenesis because it lacks glucose-6-phosphatase.- Odd-chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle (as succinyl-CoA), undergo gluconeogenesis, and serve as glucose source. Even-chain fatty acids cannot produce new glucose, since they yield only acetyl-CoA equivalents.

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