Derangement of hepatic polyamine, folate, and methionine cycle metabolism in cystathionine beta-synthase-deficient homocystinuria in the presence and absence of treatment: Possible implications for pathogenesis

Mol Genet Metab. 2021 Feb;132(2):128-138. doi: 10.1016/j.ymgme.2021.01.003. Epub 2021 Jan 11.


Cystathionine beta-synthase deficient homocystinuria (HCU) is a life-threatening disorder of sulfur metabolism. Our knowledge of the metabolic changes induced in HCU are based almost exclusively on data derived from plasma. In the present study, we present a comprehensive analysis on the effects of HCU upon the hepatic metabolites and enzyme expression levels of the methionine-folate cycles in a mouse model of HCU. HCU induced a 10-fold increase in hepatic total homocysteine and in contrast to plasma, this metabolite was only lowered by approximately 20% by betaine treatment indicating that this toxic metabolite remains unacceptably elevated. Hepatic methionine, S-adenosylmethionine, S-adenosylhomocysteine, N-acetlymethionine, N-formylmethionine, methionine sulfoxide, S-methylcysteine, serine, N-acetylserine, taurocyamine and N-acetyltaurine levels were also significantly increased by HCU while cysteine, N-acetylcysteine and hypotaurine were all significantly decreased. In terms of polyamine metabolism, HCU significantly decreased spermine and spermidine levels while increasing 5'-methylthioadenosine. Betaine treatment restored normal spermine and spermidine levels but further increased 5'-methylthioadenosine. HCU induced a 2-fold induction in expression of both S-adenosylhomocysteine hydrolase and methylenetetrahydrofolate reductase. Induction of this latter enzyme was accompanied by a 10-fold accumulation of its product, 5-methyl-tetrahydrofolate, with the potential to significantly perturb one‑carbon metabolism. Expression of the cytoplasmic isoform of serine hydroxymethyltransferase was unaffected by HCU but the mitochondrial isoform was repressed indicating differential regulation of one‑carbon metabolism in different sub-cellular compartments. All HCU-induced changes in enzyme expression were completely reversed by either betaine or taurine treatment. Collectively, our data show significant alterations of polyamine, folate and methionine cycle metabolism in HCU hepatic tissues that in some cases, differ significantly from those observed in plasma, and have the potential to contribute to multiple aspects of pathogenesis.

Keywords: Cystathionine beta-synthase; Folate cycle; Homocysteine; Homocystinuria; Methionine cycle; One‑carbon metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylhomocysteinase / genetics
  • Animals
  • Betaine / pharmacology
  • Cystathionine beta-Synthase / genetics*
  • Cystathionine beta-Synthase / metabolism
  • Disease Models, Animal
  • Folic Acid / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glycine Hydroxymethyltransferase / genetics
  • Homocysteine / blood
  • Homocysteine / metabolism
  • Homocystinuria / drug therapy
  • Homocystinuria / genetics
  • Homocystinuria / metabolism*
  • Homocystinuria / pathology
  • Humans
  • Liver / enzymology
  • Liver / metabolism*
  • Methionine / analogs & derivatives
  • Methionine / metabolism*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Mice
  • Polyamines / metabolism


  • Polyamines
  • Homocysteine
  • Betaine
  • Folic Acid
  • Methionine
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Glycine Hydroxymethyltransferase
  • Adenosylhomocysteinase
  • Cystathionine beta-Synthase