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.
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
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
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.
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
