Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression

Fundam Clin Pharmacol. 2015 Dec;29(6):522-8. doi: 10.1111/fcp.12145. Epub 2015 Sep 17.


Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression.

Keywords: depression; genetic alteration; homocysteine; neurotoxicity; neurotransmitters.

Publication types

  • Review

MeSH terms

  • Cysteine / analogs & derivatives
  • Cysteine / metabolism
  • Depression / etiology*
  • Depression / metabolism*
  • Homocysteine / analogs & derivatives
  • Homocysteine / metabolism*
  • Humans
  • Hyperhomocysteinemia / metabolism*
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxicity Syndromes / metabolism*
  • S-Adenosylmethionine / metabolism


  • Homocysteine
  • homocysteic acid
  • S-Adenosylmethionine
  • Cysteine
  • cysteine sulfinic acid