## Heme Synthesis: First Committed Step ### ALA Synthase (ALAS) **Key Point:** ALA synthase catalyzes the condensation of glycine and succinyl-CoA to form δ-aminolevulinic acid (ALA), the first committed and rate-limiting step of heme synthesis. **High-Yield:** The enzyme requires **pyridoxal phosphate (PLP)**, the active form of vitamin B₆, as an essential cofactor. ### Regulation - Located in the **mitochondrial matrix** - Feedback inhibited by heme (negative allosteric regulation) - Induced by drugs (phenobarbital, rifampicin) and fasting - Two isoforms: ALAS1 (ubiquitous, housekeeping) and ALAS2 (erythroid-specific) ### Clinical Significance **Clinical Pearl:** Deficiency or dysfunction of ALAS2 causes X-linked sideroblastic anemia due to impaired heme synthesis in erythroid cells, leading to iron accumulation in mitochondria (ringed sideroblasts on bone marrow examination). **Mnemonic:** **ALAS = A-LA-S (Amino-Levulinic-Acid Synthase)** — think "alas, we need B₆ to start heme!" [cite:Lehninger Principles of Biochemistry Ch 24]
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