SAM

**Synthesis:** Methionine + ATP → SAM, catalyzed by methionine adenosyltransferase (MAT). This is unusual because all three phosphates of ATP are released (PPi + Pi).

**Methyl transfer reactions (SAM → SAH):** - Norepinephrine → epinephrine (PNMT; induced by cortisol in the adrenal medulla) - Phosphatidylethanolamine → phosphatidylcholine - Guanidinoacetate → creatine - DNA and histone methylation (epigenetic regulation, e.g., CpG methylation and gene silencing, genomic imprinting) - Catecholamine inactivation (COMT also uses SAM) - Histamine, melatonin synthesis, and other small-molecule/xenobiotic methylation - Protein and RNA methylation (e.g., mRNA 5' cap)

**Methionine cycle:** 1. Methionine → SAM (MAT, uses ATP) 2. SAM → SAH (methyltransferases) 3. SAH → homocysteine + adenosine (SAH hydrolase) 4. Homocysteine → methionine, via homocysteine methyltransferase (methionine synthase), which needs vitamin B12 (cobalamin) and N5-methyl-THF. This links SAM to the folate cycle. The liver also has betaine-homocysteine methyltransferase (BHMT), which uses betaine. 5. Alternatively, homocysteine + serine → cystathionine (cystathionine β-synthase, B6/PLP) → cysteine (cystathionase, B6).

**Clinical correlations:** - **Vitamin B12 deficiency:** Methionine synthase is blocked, so N5-methyl-THF is trapped (the "methyl-folate trap"). This produces megaloblastic anemia, elevated homocysteine, and elevated methylmalonic acid (MMA, from impaired methylmalonyl-CoA mutase). Neurologic deficits (subacute combined degeneration) are attributed in part to impaired SAM-dependent myelin methylation. - **Folate deficiency:** Megaloblastic anemia and elevated homocysteine, but normal MMA. - **Homocystinuria:** - Most common cause is cystathionine β-synthase deficiency (B6-responsive in some patients). Features: ectopia lentis (downward and inward lens dislocation), marfanoid habitus, intellectual disability, thromboembolism, and premature atherosclerosis. Methionine is elevated and cysteine becomes essential. Treatment: B6, low-methionine diet, cysteine supplementation, betaine. - Methionine synthase deficiency or defects in B12 metabolism also raise homocysteine, but methionine is low. - **Allosteric regulation:** SAM allosterically activates cystathionine β-synthase and inhibits methylenetetrahydrofolate reductase (MTHFR). This directs homocysteine toward cysteine when methionine is plentiful. - **Other:** Elevated SAH inhibits methyltransferases (product inhibition). SAMe is also used as a supplement (depression, osteoarthritis, liver disease), but evidence is limited. SAM is also the cofactor for radical SAM enzymes and is used in polyamine synthesis (decarboxylated SAM donates aminopropyl groups for spermidine and spermine).

**High-yield mnemonic:** "SAM the methyl man" gives methyl groups to many acceptors. Methionine is the precursor, B12 and folate recycle it, and B6 diverts it to cysteine.