MAT1A

Last update 08 May 2025

Basic Info

Synonyms

AdoMet synthase 1, AMS1, MAT

+ [10]

Introduction

Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate.

100 Clinical Results associated with MAT1A

100 Translational Medicine associated with MAT1A

0 Patents (Medical) associated with MAT1A

804

Literatures (Medical) associated with MAT1A

01 Apr 2025·The FEBS Journal

SASH1 is a novel binding partner to disassemble Caskin1 tandem SAM homopolymer through heterogeneous SAM‐SAM interaction

Article

Author: Yuan, Lin ; Liu, Zhongmin ; Chen, Qiangou ; Wang, Yanhui ; Liu, Wei ; Xiao, Kang ; Wu, Cang ; Li, Jianchao ; Chen, Yu ; Ding, Yuzhen ; Wang, Ziyi

Calcium/calmodulin‐dependent serine protein kinase (CASK) interaction protein 1/2 (Caskin1/2) is essential neuronal synaptic scaffold protein in nervous system development. Knockouts of Caskin1/2 display severe deficits in novelty recognition and spatial memory. The tandem sterile alpha motif (SAM) domains of Caskin1/2, also conserved in their Drosophila homolog Ckn, are known to form homopolymers, yet their dynamic regulation mechanism remains unclear. In this study, SAM and SH3 domain‐containing protein 1 (SASH1) was first identified as a novel binding partner of Caskin1/2 through yeast two‐hybrid (Y2H) screening. The SAM‐SAM interaction between SASH1 and Caskin1 was biochemically characterized by size‐exclusion chromatography (SEC), isothermal titration calorimetry (ITC), and glutathione‐S‐transferase (GST) pull‐down and co‐immunoprecipitation (co‐IP) assays. Structural insights from AlphaFold2‐predicted models of the Caskin1‐SAMs/SASH1‐SAM1 complex, along with mutagenesis validations, revealed key residues at the end‐helix (EH)/mid‐loop (ML) interface for this interaction. More interestingly, the Caskin1‐SAMs homopolymer can be disrupted by the SAM‐SAM interaction, which was consistently verified by using sedimentation, transmission electron microscopy (TEM), and immunofluorescence (IF) staining in heterologous cell lines. In summary, our findings provide a solid biochemical basis for the Caskin1/SASH1 interaction and propose a potential mechanism for regulating Caskin1/2 homopolymerization via SAM‐SAM interactions. More importantly, the principle governing SAM homopolymer depolymerization is generalized via suggesting two distinct types of heterogeneous SAM‐SAM interactions, offering fresh insights into SAM domain‐mediated homopolymerization and depolymerization.

01 Apr 2025·Journal of Lipid Research

S-Adenosylmethionine Deficit Disrupts Very Low-Density Lipoprotein Metabolism Promoting Liver Lipid Accumulation in Mice

Article

Author: Bizkarguenaga, Maider ; Lu, Shelly C ; Castro-Espadas, Lia ; Millet, Oscar ; Hermoso-Martínez, Uxue ; Gutiérrez de Juan, Virginia ; Barbier-Torres, Lucía ; Fernández-Ramos, David ; Luque-Urbano, María R ; Mato, José M ; Lopitz-Otsoa, Fernando

Hepatic deletion of methionine adenosyltransferase-1a (Mat1a) in mice reduces S-adenosylmethionine (SAMe), a key methyl donor essential for many biological processes, which promotes the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperglycemia and reduced MAT1A expression, along with low SAMe levels, are common in MASLD patients. This study explores how Mat1a-knockout (KO) hepatocytes respond to prolonged high glucose conditions, focusing on glucose metabolism and lipid accumulation. Hepatocytes from Mat1a-KO mice were incubated in high glucose conditions overnight, allowing for analysis of key metabolic intermediates and gene expression related to glycolysis, gluconeogenesis, glyceroneogenesis, phospholipid synthesis, and very low-density lipoprotein (VLDL) secretion. SAMe deficiency in Mat1a-KO hepatocytes led to reduced protein methyltransferase-1 activity, resulting in increased expression of glycolytic enzymes (glucokinase, phosphofructokinase, and pyruvate kinase) and decreased expression of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase). These alterations led to a reduction in dihydroxyacetone phosphate (DHAP), which subsequently inhibited mammalian target of rapamycine complex 1 (mTORC1) activity. This inhibition resulted in decreased phosphatidylcholine synthesis via the CDP-choline pathway and impaired VLDL secretion, ultimately causing lipid accumulation. Thus, under high glucose conditions, SAMe deficiency in hepatocytes depletes DHAP, inhibits mTORC1 activity, and promotes lipid buildup.

01 Apr 2025·Hepatology

Epigenetic heterogeneity hotspots in human liver disease progression

Article

Author: Pham, Kien ; Robertson, Keith D ; Wagner, Ryan T ; Pyrosopoulos, Nikolaos T. ; Hlady, Ryan A ; Wang, Liguo ; Robertson, Keith D. ; Zhao, Xia ; Pyrosopoulos, Nikolaos T ; Hlady, Ryan A. ; Wagner, Ryan T. ; Liu, Chen ; El Khoury, Louis Y. ; El Khoury, Louis Y ; Jain, Dhanpat ; Luna, Aesis

Background and Aims:Disruption of the epigenome is a hallmark of human disease, including liver cirrhosis and HCC. While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target frequently mutated genes in HCC, there is an unmet need for novel therapeutics to prevent or reverse liver damage leading to hepatic tumorigenesis, which the epigenome may provide.Approach and Results:We performed genome-wide profiling of DNA methylation, copy number, and gene expression from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contributions of these processes to liver disease progression. We identified epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity is associated with increased gene expression heterogeneity. Cirrhotic regions comprise 2 distinct cohorts—one exclusively epigenetic, and the other where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (eg, HNF1A) and known tumor suppressors (eg, RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in functional screens, supporting their relevance to hepatocarcinogenesis. Moreover, epigenetic heterogeneity hotspots are linked to clinical measures of outcome.Conclusions:Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.

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MAT1A

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