One-Carbon Units Metabolism
Aminoacids Metabolism

Author: Gianpiero Pescarmona
Date: 30/05/2009


The One-Carbon Units include different groups linked to THF:

Details of folate Pathways

They are produced during the metabolism of some Aminoacids, namely:

  • Serine
  • Histidine (via N-formimidoyl-L-glutamate)

THF acts as a carrier of reactive single carbon units, which are bonded to N-5 and N-10.

Either serine or glycine can act as methylene donor, giving N5,N10-methyleneTHF. This behaves as "virtual formaldehyde" H2C=O in reactions.

The oxidation level can be changed to methyl or methenyl by reduction or oxidation; methenylTHF can be hydrolyzed to formylTHF.

These derivatives can be used in synthetic reactions as donors of single C at the appropriate oxidation level. This may be a more important role for glycine metabolism than potential delivery of single C to catabolic reactions.

SAME synthesis

Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAMe) , the principal methyl donor and, in the liver, a precursor of glutathione.
Kegg Pathway

  • MAT1A is expressed mostly in the liver
  • MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. MAT2A activity

In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This is important pathogenetically because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth.

Methionine adenosyltransferase


Regulation by hypoxia of methionine adenosyltransferase activity and gene expression in rat hepatocytes. 1998
Oxygen supply to the hepatic parenchyma is compromised by long- or short-term ethanol consumption and pathological conditions such as cirrhosis. Impairment in the production of S-adenosyl-L-methionine, the major methylating agent, occurs during hypoxia. In this study, the molecular mechanisms implicated in the regulation of S-adenosyl-L-methionine synthesis by oxygen levels were investigated


Regulation by Diet

Methyl Cycle Genomics

Google bh4+mthfr

2009-05-31T18:08:00 - Gianpiero Pescarmona

Transition state analogues in quorum sensing and SAM recycling. 2008
Schramm VL, Gutierrez JA, Cordovano G, Basu I, Guha C, Belbin TJ, Evans GB, Tyler PC, Furneaux RH.

Albert Einstein College of Medicine, Bronx, New York, NY 10805, USA.

Transition state structures can be derived from kinetic isotope effects and computational chemistry. Molecular electrostatic potential maps of transition states serve as blueprints to guide synthesis of transition state analogue inhibitors of target enzymes. 5'- Methylthioadenosine phosphorylase (MTAP) functions in the polyamine pathway by recycling methylthioadenosine (MTA) and maintaining cellular S-adenosylmethionine (SAM). Its transition state structure was used to guide synthesis of MT-DADMe-ImmA, a picomolar inhibitor that shows anticancer effects against solid tumors. Biochemical and genomic analysis suggests that MTAP inhibition acts by altered DNA methylation and gene expression patterns. A related bacterial enzyme, 5'-methylthioadenosine nucleosidase (MTAN), functions in pathways of quorum sensing involving AI-1 and AI-2 molecules. Transition states have been solved for several bacterial MTANs and used to guide synthesis of powerful inhibitors with dissociation constants in the femtomolar to picomolar range. BuT-DADMe-ImmA blocks quorum sensing in Vibrio cholerae without changing bacterial growth rates. Transition state analogue inhibitors show promise as anticancer and antibacterial agents.

Interconnection of the pathways of DNA methylation and the polyamine interconversion cycle

Essential SUMO Pathway

Methionine and cancer W

Illustration 1. Methionine, homocysteine, and creatine metabolism. Enzymes marked with an asterisk are those with known deficiencies. (dashed line) Feedback control. AGAT = arginine-guanidinoacetate amidino methyltransferase; cbl I = cobalamin in redox state I; cbl II = cobalamin in redox state II; GAMT = guanidinoacetate methyltransferase; THF = tetrahydrofolate.

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