title: Enzymatic activity of methionine adenosyltransferase variants identified in patients with persistent hypermethioninemia.
abstract: Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been conserved with a high degree of homology among species. In the liver, MAT I and III, tetrameric and dimeric isoforms of the same catalytic subunit encoded by the gene MAT1A, account for the predominant portion of total body synthesis of S-adenosylmethionine (SAM), a versatile sulfonium ion-containing molecule involved in a variety of vital metabolic reactions and in the control of hepatocyte proliferation and differentiation. During the past 15years 28 MAT1A mutations have been described in patients with elevated plasma methionines, total homocysteines at most only moderately elevated, and normal levels of tyrosine and other aminoacids. In this study we describe functional analyses that determine the MAT and tripolyphosphatase (PPPase) activities of 18 MAT1A variants, six of them novel, and none of them previously assayed for activity. With the exception of G69S and Y92H, all recombinant proteins showed impairment (usually severe) of MAT activity. Tripolyphosphate (PPPi) hydrolysis was decreased only in some mutant proteins but, when it was decreased MAT activity was always also impaired.
authors.affiliation: Division of Hepatology and Gene Therapy, Proteomics Unit, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Fernández-Irigoyen
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaría
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
authors.forename: Hanna
authors.initials: H
authors.lastname: Faghfoury
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
authors.forename: George E
authors.initials: GE
authors.lastname: Hoganson
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
authors.forename: S Harvey
authors.initials: SH
authors.lastname: Mudd
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000097:blood*; D008716:Methionine Adenosyltransferase / Q000235:genetics* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D008715:Methionine; D008716:Methionine Adenosyltransferase; D017766:Acid Anhydride Hydrolases; C023193:tripolyphosphatase