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. 1995 Oct;96(4):1943–1947. doi: 10.1172/JCI118240

Molecular mechanisms of an inborn error of methionine pathway. Methionine adenosyltransferase deficiency.

T Ubagai 1, K J Lei 1, S Huang 1, S H Mudd 1, H L Levy 1, J Y Chou 1
PMCID: PMC185831  PMID: 7560086

Abstract

Methionine adenosyltransferase (MAT) is a key enzyme in transmethylation, transsulfuration, and the biosynthesis of polyamines. Genetic deficiency of alpha/beta-MAT causes isolated persistent hypermethioninemia and, in some cases, unusual breath odor or neural demyelination. However, the molecular mechanism(s) underlying this deficiency has not been clearly defined. In this study, we characterized the human alpha/beta-MAT transcription unit and identified several mutations in the gene of patients with enzymatically confirmed diagnosis of MAT deficiency. Site-directed mutagenesis and transient expression assays demonstrated that these mutations partially inactivate MAT activity. These results establish the molecular basis of this disorder and allow for the development of DNA-based methodologies to investigate and diagnose hypermethioninemic individuals suspected of having abnormalities at this locus.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alvarez L., Corrales F., Martín-Duce A., Mato J. M. Characterization of a full-length cDNA encoding human liver S-adenosylmethionine synthetase: tissue-specific gene expression and mRNA levels in hepatopathies. Biochem J. 1993 Jul 15;293(Pt 2):481–486. doi: 10.1042/bj2930481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. CATONI G. L. S-Adenosylmethionine; a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate. J Biol Chem. 1953 Sep;204(1):403–416. [PubMed] [Google Scholar]
  3. Cabrero C., Puerta J., Alemany S. Purification and comparison of two forms of S-adenosyl-L-methionine synthetase from rat liver. Eur J Biochem. 1987 Dec 30;170(1-2):299–304. doi: 10.1111/j.1432-1033.1987.tb13699.x. [DOI] [PubMed] [Google Scholar]
  4. Finkelstein J. D., Kyle W. E., Martin J. J. Abnormal methionine adenosyltransferase in hypermethioninemia. Biochem Biophys Res Commun. 1975 Oct 27;66(4):1491–1497. doi: 10.1016/0006-291x(75)90527-6. [DOI] [PubMed] [Google Scholar]
  5. Gahl W. A., Bernardini I., Finkelstein J. D., Tangerman A., Martin J. J., Blom H. J., Mullen K. D., Mudd S. H. Transsulfuration in an adult with hepatic methionine adenosyltransferase deficiency. J Clin Invest. 1988 Feb;81(2):390–397. doi: 10.1172/JCI113331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gahl W. A., Finkelstein J. D., Mullen K. D., Bernardini I., Martin J. J., Backlund P., Ishak K. G., Hoofnagle J. H., Mudd S. H. Hepatic methionine adenosyltransferase deficiency in a 31-year-old man. Am J Hum Genet. 1987 Jan;40(1):39–49. [PMC free article] [PubMed] [Google Scholar]
  7. Gaull G. E., Tallan H. H., Lonsdale D., Przyrembel H., Schaffner F., von Bassewitz D. B. Hypermethioninemia associated with methionine adenosyltransferase deficiency: clinical, morphologic, and biochemical observations on four patients. J Pediatr. 1981 May;98(5):734–741. doi: 10.1016/s0022-3476(81)80833-5. [DOI] [PubMed] [Google Scholar]
  8. Gaull G. E., Tallan H. H. Methionine adenosyltransferase deficiency: new enzymatic defect associated with hypermethioninemia. Science. 1974 Oct 4;186(4158):59–60. doi: 10.1126/science.186.4158.59. [DOI] [PubMed] [Google Scholar]
  9. Gout J. P., Serre J. C., Dieterlen M., Antener I., Frappat P., Bost M., Beaudoing A. Une nouvelle cause d'hyperméthioninémie de l'enfant: le deficit en S-adenosyl-méthionine-synthétase. Arch Fr Pediatr. 1977 May;34(5):416–423. [PubMed] [Google Scholar]
  10. Horikawa S., Ozasa H., Ota K., Tsukada K. Immunohistochemical analysis of rat S-adenosylmethionine synthetase isozymes in developmental liver. FEBS Lett. 1993 Sep 20;330(3):307–311. doi: 10.1016/0014-5793(93)80894-z. [DOI] [PubMed] [Google Scholar]
  11. Horikawa S., Tsukada K. Molecular cloning and developmental expression of a human kidney S-adenosylmethionine synthetase. FEBS Lett. 1992 Nov 2;312(1):37–41. doi: 10.1016/0014-5793(92)81405-b. [DOI] [PubMed] [Google Scholar]
  12. Horikawa S., Tsukada K. Molecular cloning and nucleotide sequence of cDNA encoding the human liver S-adenosylmethionine synthetase. Biochem Int. 1991 Sep;25(1):81–90. [PubMed] [Google Scholar]
  13. Kotb M., Geller A. M. Methionine adenosyltransferase: structure and function. Pharmacol Ther. 1993 Aug;59(2):125–143. doi: 10.1016/0163-7258(93)90042-c. [DOI] [PubMed] [Google Scholar]
  14. Kotb M., Kredich N. M. S-Adenosylmethionine synthetase from human lymphocytes. Purification and characterization. J Biol Chem. 1985 Apr 10;260(7):3923–3930. [PubMed] [Google Scholar]
  15. Mitsui K., Teraoka H., Tsukada K. Complete purification and immunochemical analysis of S-adenosylmethionine synthetase from bovine brain. J Biol Chem. 1988 Aug 15;263(23):11211–11216. [PubMed] [Google Scholar]
  16. Mount S. M. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. doi: 10.1093/nar/10.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Okada G., Teraoka H., Tsukada K. Multiple species of mammalian S-adenosylmethionine synthetase. Partial purification and characterization. Biochemistry. 1981 Feb 17;20(4):934–940. doi: 10.1021/bi00507a045. [DOI] [PubMed] [Google Scholar]
  18. Orita M., Iwahana H., Kanazawa H., Hayashi K., Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. doi: 10.1073/pnas.86.8.2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sakata S. F., Shelly L. L., Ruppert S., Schutz G., Chou J. Y. Cloning and expression of murine S-adenosylmethionine synthetase. J Biol Chem. 1993 Jul 5;268(19):13978–13986. [PubMed] [Google Scholar]
  20. Sullivan D. M., Hoffman J. L. Fractionation and kinetic properties of rat liver and kidney methionine adenosyltransferase isozymes. Biochemistry. 1983 Mar 29;22(7):1636–1641. doi: 10.1021/bi00276a017. [DOI] [PubMed] [Google Scholar]
  21. Surtees R., Leonard J., Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet. 1991 Dec 21;338(8782-8783):1550–1554. doi: 10.1016/0140-6736(91)92373-a. [DOI] [PubMed] [Google Scholar]
  22. Tallan H. H., Cohen P. A. Methionine adenosyltransferase: kinetic properties of human and rat liver enzymes. Biochem Med. 1976 Dec;16(3):234–250. doi: 10.1016/0006-2944(76)90029-6. [DOI] [PubMed] [Google Scholar]

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