oxidative decarboxylation

**Definition:** A reaction that removes a carboxyl group as CO2 and oxidizes the substrate at the same time. The electrons are transferred to NAD+ (producing NADH). For alpha-keto acids, the product is an acyl-CoA that is one carbon shorter.

**Key examples (all irreversible, all use the same cofactors):** 1. **Pyruvate dehydrogenase complex (PDH):** Pyruvate + NAD+ + CoA → Acetyl-CoA + CO2 + NADH. It occurs in the mitochondrial matrix and links glycolysis to the TCA cycle. 2. **Alpha-ketoglutarate dehydrogenase complex:** α-KG + NAD+ + CoA → Succinyl-CoA + CO2 + NADH. This is a TCA cycle step. 3. **Branched-chain alpha-ketoacid dehydrogenase (BCKDH):** This enzyme acts on the keto acids derived from valine, leucine, and isoleucine. 4. **Isocitrate dehydrogenase** (isocitrate → α-KG) is also an oxidative decarboxylation. It is the rate-limiting step of the TCA cycle. **Malic enzyme** (malate → pyruvate, producing NADPH) and **6-phosphogluconate dehydrogenase** in the HMP shunt (producing NADPH) are other examples.

**Enzyme complex structure (PDH, α-KGDH, and BCKDH):** - **E1** (decarboxylase) uses **thiamine pyrophosphate (TPP, B1)**. - **E2** (transacetylase) uses **lipoic acid** and **CoA (pantothenate, B5)**. - **E3** (dihydrolipoyl dehydrogenase) uses **FAD (B2)** and **NAD+ (B3)**. - Mnemonic: "Tired Lovers For Coenzyme A" = TPP, Lipoate, FAD, CoA, plus NAD+. - The three complexes are structurally and mechanistically similar. They share E3, and PDH and α-KGDH share the same cofactors.

**Regulation of PDH:** - PDH is activated by pyruvate, ADP, NAD+, CoA, and Ca2+. Insulin also activates it indirectly through PDH phosphatase. - It is inhibited by acetyl-CoA, NADH, and ATP. - PDH kinase phosphorylates and inactivates the complex. PDH phosphatase dephosphorylates and activates it.

**Clinical correlations:** - **PDH deficiency:** It is usually X-linked (E1-α subunit). Pyruvate is shunted to lactate (via LDH) and to alanine (via ALT). This causes **lactic acidosis**, elevated alanine, neurologic defects, and failure to thrive. Brain energy is impaired. Treatment is a **ketogenic diet** with high fat and ketone-forming amino acids (**lysine and leucine** are purely ketogenic). Thiamine may help in some cases. - **Thiamine (B1) deficiency (beriberi, Wernicke-Korsakoff):** TPP is needed for PDH, α-KGDH, BCKDH, and transketolase. The result is impaired ATP production, lactic acidosis, and neurologic and cardiac dysfunction. Giving glucose before thiamine to alcoholic patients can precipitate or worsen Wernicke encephalopathy. - **Maple syrup urine disease:** Defective BCKDH causes accumulation of branched-chain amino acids (Leu, Ile, Val) and their keto acids. Features are sweet-smelling urine, poor feeding, and neurologic damage. Treatment is a diet restricted in branched-chain amino acids, with thiamine supplementation in some patients. - **Arsenic poisoning:** Arsenic inhibits **lipoic acid** and so inhibits PDH and α-KGDH. Features are vomiting, "rice-water" diarrhea, garlic breath, and QT prolongation. - **Other inhibitors:** Lipoic acid is inhibited by arsenic. PDH is also inhibited by **mercury**. - **Alcoholism:** Thiamine deficiency plus increased NADH inhibit PDH. Pyruvate is converted to lactate.

**Key pearls:** - Oxidative decarboxylation forms **NADH** (except malic enzyme and 6-phosphogluconate DH, which form **NADPH**). - Substrate-level phosphorylation in the TCA cycle follows α-KGDH (succinyl-CoA → succinate, producing GTP or ATP). - These reactions are irreversible. Animals cannot convert acetyl-CoA back to pyruvate, so fatty acids cannot be converted to glucose.