CoA

STRUCTURE: CoA = 3',5'-ADP + phosphopantetheine (from pantothenic acid, B5) + cysteamine (β-mercaptoethylamine). The reactive -SH (thiol) of cysteamine forms a thioester with acyl groups (R-CO-S-CoA). Thioesters have a high negative ΔG of hydrolysis (about -7.5 kcal/mol, similar to ATP), so the acyl group is "activated" for transfer. Phosphopantetheine is also the prosthetic group of the acyl carrier protein (ACP) domain of fatty acid synthase.

KEY ACYL-CoA SPECIES: - Acetyl-CoA: from pyruvate (pyruvate dehydrogenase), β-oxidation, ketogenic amino acids, and ethanol metabolism. Enters the TCA cycle (condenses with oxaloacetate via citrate synthase). Substrate for fatty acid, cholesterol, and ketone body synthesis. Also the acetyl donor for acetylcholine (choline acetyltransferase) and histone acetylation. - Succinyl-CoA: TCA cycle (α-ketoglutarate dehydrogenase); from odd-chain fatty acid/branched-chain amino acid catabolism via propionyl-CoA → methylmalonyl-CoA (needs B12) → succinyl-CoA. Used for heme synthesis (ALA synthase, with B6) and ketone body activation. - Malonyl-CoA: made by acetyl-CoA carboxylase (biotin, ATP; rate-limiting step of fatty acid synthesis). It inhibits carnitine acyltransferase I (CPT-I), preventing futile cycling of β-oxidation. - Acyl-CoA/fatty acyl-CoA: fatty acids are activated by acyl-CoA synthetase (thiokinase) on the outer mitochondrial membrane, then shuttled by the carnitine shuttle (CPT-I, rate-limiting for β-oxidation). - HMG-CoA: used for ketogenesis (HMG-CoA synthase, mitochondrial) and cholesterol synthesis (HMG-CoA reductase, cytosolic; inhibited by statins). - Propionyl-CoA: carboxylated by propionyl-CoA carboxylase (biotin).

REGULATION: Acetyl-CoA allosterically activates pyruvate carboxylase (gluconeogenesis) and inhibits pyruvate dehydrogenase (indirectly, by activating PDH kinase), which favors gluconeogenesis during fasting. Fatty acid oxidation raises the acetyl-CoA/CoA ratio.

CLINICAL CORRELATIONS: - Pyruvate dehydrogenase complex requires 5 cofactors: thiamine (B1, TPP), lipoate, CoA (B5), FAD (B2), and NAD+ (B3). Mnemonic: "Tired Lovers For Nighttime Companionship" (TPP, lipoic acid, FAD, NAD, CoA). Deficiency of PDH causes lactic acidosis and neurologic defects. Treatment is a ketogenic diet (high fat, lysine and leucine). - Arsenic poisoning inhibits lipoic acid, which impairs PDH and α-ketoglutarate dehydrogenase. - Pantothenic acid (B5) deficiency is rare. It causes burning feet syndrome (paresthesias), fatigue, and adrenal insufficiency-like symptoms. Pantothenate kinase deficiency (PKAN, NBIA type 1) is a disorder of CoA biosynthesis, with iron accumulation in the globus pallidus ("eye of the tiger" sign on MRI). - Methylmalonic acidemia/aciduria (methylmalonyl-CoA mutase deficiency or B12 deficiency) and propionic acidemia (propionyl-CoA carboxylase deficiency) cause metabolic acidosis, hyperammonemia, and vomiting in neonates. - MCAD deficiency (medium-chain acyl-CoA dehydrogenase) causes hypoketotic hypoglycemia, with dicarboxylic aciduria. It is the most common fatty acid oxidation disorder. - Primary carnitine deficiency impairs transport of acyl-CoA into mitochondria and causes hypoketotic hypoglycemia and cardiomyopathy. - Acetyl-CoA is a key link between carbohydrate, lipid, and amino acid metabolism. In prolonged fasting or uncontrolled diabetes, excess acetyl-CoA (with oxaloacetate depleted for gluconeogenesis) is shunted to ketone body production.

HIGH-YIELD POINT: "CoA" is the carrier, and the "acetyl" is the cargo. Acetyl-CoA = activated 2-carbon unit.