USMLE (Fach) / Biochemistry - Metabolism (Lektion)

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• Sorbitol An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart, sorbitol, via aldose reductase. Some tissues then convert sorbitol to fructose using sorbitol dehydrogenase. Tissues with an insufficient amount/activity of sorbitol dehydrogenase are at risk of intracellular sorbitol accumulation, causing osmotic damage (eg, cataracts, retinopathy, and peripheral neuropathy seen with chronic hyperglycemia in diabetes). High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose reductase. Glucose –(Aldose reductase, NADPH)→ Sorbitol –(Sorbitol dehydrogenase)→ Fructose Liver, ovaries, and seminal vesicles have both enzymes.Lens has primarily aldose reductase.Retina, kidneys, and Schwann cells have only aldose reductase.
• Amino acids Only L-amino acids are found in proteins. Essential: Phenylalanine, valine, tryptophan, threonine, isoleucine, methionine, histidine, leucine, lysine- Glucogenic: Methionine, histidine, valine- Glucogenic/ketogenic: Isoleucine, phenylalanine, threonine, tyrosine- Ketogenic: Leucine, lysine Acidic: Aspartic acid, glutamic acid Basic: Arginine, histidine, lysine- Arginine and histidine are required during periods of growth.- Arginine and lysine are ↑ in histones which bind negatively charged DNA.
• Lysosomal storage diseases - Mucopolysaccharidoses Hurler syndrome:- Deficient enzyme: α-Iduronidase- Accumulated substance: Heparan sulfate, dermatan sulfate- Findings: Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly Hunter syndrome: X-linked recessive- Deficient enzyme: Iduronate-2-sulfatase- Accumulated substance: Heparan sulfate, dermatan sulfate- Findings: Mild Hurler + aggressive behavior, no cornea clouding
• Key enzymes in lipid transport Cholesteryl ester transfer protein (CETP) mediates transfer of cholesterol esters (mature HDLs) to other lipoprotein particles (VDLD, IDL, LDL). Hepatic lipase: Degrades TGs remaining in IDL. Hormone-sensitive lipase: Degrades TGs stored in adipocytes. Lipoprotein lipase: Degrades TGs in circulating chylomicrons and VLDLs. Found on vascular endothelial surface. Lecithin-cholesterol acyltransferase: Catalyzes esterification of 2/3 of plasma cholesterol. Only on HDLs. Pancreatic lipase: Degrades dietary TGs in small intestine. PCSK9: Degrades LDL receptor → ↑ serum LDL. Inhibition → ↑ recycling of LDL receptor → ↓ serum LDL.
• Abetalipoproteinemia Autosomal recessive. Mutation in gene that encodes microsomal transfer protein (MTP). - Chylomicrons, VLDL, LDL absent. Deficiency in ApoB-48, ApoB-100. - ↓ triglyceride and cholesterol levels - Affected infants present with severe fat malabsorption, steatorrhea, failure to thrive.- Later manifestations include retinitis pigmentosa, spinocerebellar degeneration due to vitamin E deficiency, progressive ataxia, acanthocytosis.- Intestinal biopsy shows lipid-laden enterocytes. Treatment: Restriction of long-chain fatty acids, large doses of oral vitamin E.
• ATP yielding reactions in glycolysis 1,3-Bisphosphoglycerate –Phosphoglycerate kinase→ 3-Phosphoglycerate Phosphoenolpyruvate (PEP) –Pyruvate kinase→ Pyruvate
• ATP-consuming reactions in glycolysis Glucose –Hexokinase/Glucokinase→ Glucose-6P Fructose-6P –Phosphofructokinase-1→ Fructose-1,6-bisphosphonate
• NAD+ consuming reaction in glycolysis Glyceraldehyd-3P –Glyceraldehyd-3P dehydrogenase→ 1,3-Bisphosphoglycerate
• Lactate dehydrogenase - Used only in anaerobic glycolysis - Reoxidizes NADH to NAD, replenishing the oxidized coenzyme for glyceraldehyd 3-phosphate dehydrogenase.
• Pyruvate kinase Last enzyme in glycolysis, it catalyzes phosphorylation of ADP using the high-energy substrate phosphoenolpyruvate (PEP). - Activated by fructose-1,6-bisphosphate from the PFK-1 reaction (feed-forward activation).
• NADH shuttles The inner mitochondrial membrane is impermeable to NADH.Cytoplasmic NADH is reoxidized to NAD and delivers its electrons to one of two electron shuttles in the inner membrane: 1. Cytoplasmic NADH oxidized using the malate shuttle produces mitochondrial NADH and yields approximately 3 ATP by oxidative phosphorylation.- In heart and liver 2. Cytoplasmic NADH oxidized by the glycerol phosphate shuttle produces a mitochondrial FADH2 and yield approximately 2 ATP by oxidative phosphorylation.- In muscle
• Activated carriers ATP – Phosphoryl groupsNADH, NADPH, FADH2 – ElectronsCoA, lipoamide – Acyl groupsBiotin – CO2Tetrahydrofolates – 1-carbon unitsS-adenosylmethionine (SAM) – CH3 groupsTPP – Aldehydes
• Universal electron acceptors Nicotinamides (NAD+, NADP+ from vitamin B3) and flavin nucleotides (FAD+ from vitamin B2). NAD+ is generally used in catabolic processes to carry reducing equivalents away as NADH. NADPH is used in anabolic processes (eg, steroid and fatty acid synthesis) as a supply of reducing equivalents.- NADPH is a produce of the HMP shunt- NADPH is used in anabolic processes, respiratory burst, cytochrome P-450 system, glutathione reductase
• GTP-yielding reaction in TCA cycle Succinyl-CoA –Succinyl-CoA synthetase (succinate thiokinase)→ Succinate
• FADH2-yieling reaction in TCA Succinate –Succinate dehydrogenase (complex II)→ Fumarate
• NADH-yielding reactions in TCA Isocitrate –Isocitrate dehydrogenase → α-Ketoglutarate α-Ketoglutarate –α-Ketoglutarate dehydrogenase→ Succinyl-CoA Malate –Malate dehydrogenase→ Oxaloacetate
• Uncoupling agents - 2,4-dinitrophenol (2,4-DNP) - Aspirin (high-dose) - UCP/thermogenin (natural uncoupling protein in brown fat)
• Glycogen storage disease type I (von Gierke) Deficiency of glucose-6-phosphatase Presentation:- Severe fasting hypoglycemia- Lactic acidosis- Hepatomegaly- Doll-like facies- Protruding abdomen - ↑↑ glycogen deposits in the liver and kidneys- ↑ blood lactate- ↑ triglycerids with skin xanthomas- ↑ uric acid predisposing to gout (decreased Pi causes increased AMP, which is degraded to uric acid) - Ingestion of galactose or fructose causes no increase in blood glucose, nor does administration of glucagon! Treatment: frequent oral glucose/cornstarch; avoidance of fructose and galactose
• Glycogen storage disease type II (Pompe) Deficient enzyme: Lysosomal acid α-1,4-glucosidase with α-1,6 glucosidase activity (acid maltase) Presentation:- Cardiomegaly- Hypertrophic cardiomyopathy- Hypotonia- Exercise intolerance- Peripheral edema- Early death ECG shows short PR intervals with large QRS complexes signaling biventricular hypertrophy.
• Glycogen storage disease type III (Cori) Deficient enzyme: Debranching enzyme (α-1,6-glucosidase) Presentation:- Milder form of von Gierke (type I) with normal lactate levels- Mild hypoglycemia- Hepatomegaly - Accumulation of limit dextrin-like structures in cytosol.
• Glycogen storage disease type V (McArdle) Deficient enzyme: Skeletal muscle glycogen phosphorylase (myophosphorylase) Presentation:- ↑ glycogen in muscle, but muscle cannot break it down → painful muscle cramps- Myoglobinuria (red urine) with strenuous exercise- Arrhythmia from electrolyte abnormalities- Second-wind phenomenon noted during exercise due to ↑ muscular blood flow. - Hallmark is a flat venous lactate curve with normal rise in ammonia levels during exercise.- Blood glucose levels typically unaffected (liver glycogenolysis unaffected)
• Alcoholism Alcoholics are very susceptible to hypoglycemia. In addition to poor nutrition and the fact that alcohol is metabolized to acetate (acetyl-CoA), the high amounts of cytoplasmic NADH formed by alcohol dehydrogenase and acetaldehyde dehydrogenase interfere with gluconeogenesis. High NADH favors the formation of:- Pyruvate → Lactate- Oxaloacetate → Malate in the cytoplasm- Glycerol 3-phosphate from DHAP
• Proprionic acid pathway Odd-carbon fatty acids yield one acetyl-CoA and one propionyl-CoA form the 5-carbon fragment remaining. Propionyl-CoA is converted to methylmalonyl-CoA and then to succinyl-CoA, a TCA cycle intermediate.→ Odd-carbon fatty acids except an exception to the rule that fatty acids cannot be converted to glucose. Propionyl-CoA carboxylase requires biotin.Methylmalonyl-CoA mutase requires vitamin B12.
• Classes of sphingolipids - Sphingomyelin: Ceramide + Phosphorylcholine - Cerebrosides: Ceramide + galactose or glucose Gangliosides: Ceramide + oligosaccharides + sialic acid
• Arginase deficiency Absent or nonfunctional arginase enzyme → impaired conversion of arginine to ornithineAutosomal recessive - Progressive development of spastic diplegia, abnormal movements, growth delay- Elevated arginine levels- Unlike other urea cycle disorders, mild or no hyperammonemia Treatment: low-protein diet devoid of arginine
• Primary carnitine deficiency Defect in the protein responsible for carnitine transport across the mitochondrial membrane. Without sufficienct carnitine, fatty acids cannot be transported from the cytoplasm into the mitochondria as acyl-carnitine (carnitine shuttle). The mitochondria therefore cannot β-oxidize the fatty acids into acetyl CoA, the carbon substrate for the citric acid cycle. As a result, cardiac and skeletel myocytes cannot generate ATP from fatty acids (leading to muscle weakness, cardiomyopathy) and the liver is unable to synthesize ketone bodies. - Myopathy (eg, ↑ CK, weakness)- Cardiomyopathy (eg, S3 gallop)- Hypoketotic hypoglycemia- Decreased muscle carnitine
• BH4 (tetrahydrobiopterin) Involved in reactions: Phenylalanine → TyrosineTyrosine → DOPA Tryptophan → Serotonin (+B6) Arginine → Nitric oxide

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