A Glycine N-methyltransferase Knockout Mouse Model for Humans with Deficiency of This Enzyme

Overview

Journal Transgenic Res

Specialty Molecular Biology

Date 2006 Jun 17

PMID 16779654

Citations 58

Authors

Zigmund Luka

Antonieta Capdevila

Jose M Mato

C Wagner

Affiliations

Soon will be listed here.

Abstract

Three human cases having mutations in the glycine N-methyltransferase (GNMT) gene have been reported. This enzyme transfers a methyl group from S-adenosylmethionine (SAM) to glycine to form S-adenosylhomocysteine (SAH) and N-methylglycine (sarcosine) and is believed to be involved in the regulation of methylation. All three cases have mild liver disease but they seem otherwise unaffected. To study this further, gnmt deficient mice were generated for the first time. This resulted in the complete absence of GNMT protein and its activity in livers of homozygous mice. Compared to WT animals the absence of GNMT resulted in up to a 7-fold increase of free methionine and up to a 35-fold increase of SAM. The amount of SAH was significantly decreased (3 fold) in the homozygotes compared to WT. The ratio of SAM/SAH increased from 3 in WT to 300 in livers of homozygous transgenic mice. This suggests a possible significant change in methylation in the liver and other organs where GNMT is expressed.

Citing Articles

The complex role of glycine N-methyltransferase in metabolism-a review.

Suzauddula M, Islam M, Ahmed T Mol Biol Rep. 2025; 52(1):271.

PMID: 40025311 DOI: 10.1007/s11033-025-10374-w.

The Pivotal Role of One-Carbon Metabolism in Neoplastic Progression During the Aging Process.

Majumder A, Bano S, Nayak K Biomolecules. 2024; 14(11).

PMID: 39595564 PMC: 11591851. DOI: 10.3390/biom14111387.

Serine metabolism in aging and age-related diseases.

Shan S, Hoffman J Geroscience. 2024; 47(1):611-630.

PMID: 39585647 PMC: 11872823. DOI: 10.1007/s11357-024-01444-1.

Transcriptional control of a metabolic switch regulating cellular methylation reactions is part of a common response to stress in divergent bee species.

Kogan H, Macleod S, Rondeau N, Raup-Collado J, Cordero V, Rovnyak D J Exp Biol. 2024; 227(11).

PMID: 38736357 PMC: 11415054. DOI: 10.1242/jeb.246894.

Paracetamol toxicity in classic homocystinuria: Effect of -acetylcysteine on total homocysteine.

Elkhateeb N, Hyde S, Hogg S, Allsop D, Shankar A, Deegan P JIMD Rep. 2023; 64(3):238-245.

PMID: 37151359 PMC: 10159864. DOI: 10.1002/jmd2.12363.

References

Mudd S, Cerone R, Schiaffino M, Fantasia A, Minniti G, Caruso U . Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. J Inherit Metab Dis. 2001; 24(4):448-64. DOI: 10.1023/a:1010577512912. View

Luka Z, Cerone R, Phillips 3rd J, Mudd H, Wagner C . Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Hum Genet. 2002; 110(1):68-74. DOI: 10.1007/s00439-001-0648-4. View

Augoustides-Savvopoulou P, Luka Z, Karyda S, Stabler S, Allen R, Patsiaoura K . Glycine N -methyltransferase deficiency: a new patient with a novel mutation. J Inherit Metab Dis. 2004; 26(8):745-59. DOI: 10.1023/B:BOLI.0000009978.17777.33. View

Pakhomova S, Luka Z, Grohmann S, Wagner C, Newcomer M . Glycine N-methyltransferases: a comparison of the crystal structures and kinetic properties of recombinant human, mouse and rat enzymes. Proteins. 2004; 57(2):331-7. DOI: 10.1002/prot.20209. View

Suzuki N, Wagner C . Purification and characterization of a folate binding protein from rat liver cytosol. Arch Biochem Biophys. 1980; 199(1):236-48. DOI: 10.1016/0003-9861(80)90277-5. View

Cook R, Wagner C . Glycine N-methyltransferase is a folate binding protein of rat liver cytosol. Proc Natl Acad Sci U S A. 1984; 81(12):3631-4. PMC: 345272. DOI: 10.1073/pnas.81.12.3631. View

Wagner C, Briggs W, Cook R . Inhibition of glycine N-methyltransferase activity by folate derivatives: implications for regulation of methyl group metabolism. Biochem Biophys Res Commun. 1985; 127(3):746-52. DOI: 10.1016/s0006-291x(85)80006-1. View

Finkelstein J, Martin J . Methionine metabolism in mammals. Adaptation to methionine excess. J Biol Chem. 1986; 261(4):1582-7. View

Tybulewicz V, Crawford C, Jackson P, Bronson R, Mulligan R . Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991; 65(7):1153-63. DOI: 10.1016/0092-8674(91)90011-m. View

10.

Balaghi M, Horne D, Wagner C . Hepatic one-carbon metabolism in early folate deficiency in rats. Biochem J. 1993; 291 ( Pt 1):145-9. PMC: 1132493. DOI: 10.1042/bj2910145. View

11.

Yeo E, Wagner C . Tissue distribution of glycine N-methyltransferase, a major folate-binding protein of liver. Proc Natl Acad Sci U S A. 1994; 91(1):210-4. PMC: 42916. DOI: 10.1073/pnas.91.1.210. View

12.

Ogawa H, Gomi T, Fujioka M . Mammalian glycine N-methyltransferases. Comparative kinetic and structural properties of the enzymes from human, rat, rabbit and pig livers. Comp Biochem Physiol B. 1993; 106(3):601-11. DOI: 10.1016/0305-0491(93)90137-t. View

13.

Fu Z, Hu Y, Konishi K, Takata Y, Ogawa H, Gomi T . Crystal structure of glycine N-methyltransferase from rat liver. Biochemistry. 1996; 35(37):11985-93. DOI: 10.1021/bi961068n. View

14.

Aida K, Tawata M, Negishi M, Onaya T . Mouse glycine N-methyltransferase is sexually dimorphic and regulated by growth hormone. Horm Metab Res. 1998; 29(12):646-9. DOI: 10.1055/s-2007-978982. View

15.

Pattanayek R, Newcomer M, Wagner C . Crystal structure of apo-glycine N-methyltransferase (GNMT). Protein Sci. 1998; 7(6):1326-31. PMC: 2144038. DOI: 10.1002/pro.5560070608. View

16.

Capdevila A, Wagner C . Measurement of plasma S-adenosylmethionine and S-adenosylhomocysteine as their fluorescent isoindoles. Anal Biochem. 1998; 264(2):180-4. DOI: 10.1006/abio.1998.2839. View

17.

Mato J, Corrales F, Martin-Duce A, Ortiz P, Pajares M, Cabrero C . Mechanisms and consequences of the impaired trans-sulphuration pathway in liver disease: Part I. Biochemical implications. Drugs. 1990; 40 Suppl 3:58-64. DOI: 10.2165/00003495-199000403-00006. View