Ask about this productRelated genes to: C2orf25 antibody
- Gene:
- MMADHC NIH gene
- Name:
- metabolism of cobalamin associated D
- Previous symbol:
- C2orf25
- Synonyms:
- CL25022, cblD
- Chromosome:
- 2q23.2
- Locus Type:
- gene with protein product
- Date approved:
- 2004-04-29
- Date modifiied:
- 2018-08-02
Related products to: C2orf25 antibody
Related articles to: C2orf25 antibody
- Human methionine synthase (MTR) is an essential enzyme of one carbon metabolism. Consisting of a catalytic N-half and a cobalamin binding C-half, MTR utilises this intricate organometallic cofactor in the methyl transfer from methyltetrahydrofolate to homocysteine producing methionine. Cobalamin loading into MTR, and its subsequent activation, requires methylmalonic aciduria and homocystinuria Type D (MMADHC) protein and methionine synthase reductase (MTRR), respectively. However, the molecular basis of cobalamin binding and activation of human MTR aided by MMADHC and MTRR remains unknown. Here, using cryo-electron microscopy, we determine structures of human MTR in its apo, and cobalamin bound states. Apo MTR adopts a conformation where the two halves of the enzyme act independently with the C-half posed to bind cobalamin. Binding of cobalamin and its activation causes conformational changes in MTR that result in a flexible catalytically active state. AlphaFold predictions, validated by interaction studies, show that MMADHC interacts with the C-half of apo MTR to facilitate cobalamin loading. Unexpectedly we found that MTRR interacts at two distinct sites within the C-half of MTR which may aid in activation. Collectively these findings lay the groundwork to uncover the mechanisms through how MMADHC and MTRR coordinate cobalamin loading and activation of human MTR. - Source: PubMed
Publication date: 2026/05/11
Ferreira Douglas S MMcLennan KatieDiamond CalumVollmar MelanieKiyani WasimFroese D SeanKopec JolaBailey Henry JChalk RodBaslé ArnaudElkins Jonathan MCoker Jesse AYue Wyatt WMcCorvie Thomas J - : Isolated methylmalonic acidemia (iMMA) is a rare autosomal recessive metabolic disorder caused by defects in methylmalonyl-CoA mutase (MCM) activity or in the biosynthesis of its cofactor, adenosylcobalamin. Mutations in five genes-, , , , and -are known to underlie this condition. This study aimed to characterize the clinical features and molecular spectrum of iMMA in Malaysian patients of diverse ethnic backgrounds. : Patients with biochemical evidence suggestive of iMMA, including elevated propionylcarnitine (C3), increased C3/C2 ratio, and raised urine methylmalonic acid levels in the absence of hyperhomocysteinemia, were selected for genetic testing. Sanger sequencing was performed to identify pathogenic variants in the , , , , or genes. : The cohort consisted predominantly of Iban patients ( = 5), with the remaining cases comprising one Malay and one Thai-Malay individual. Age at diagnosis ranged from Day 1 of life to 6 years. All 7 patients were confirmed to have iMMA through molecular analysis. A total of seven pathogenic or likely pathogenic variants were identified, including two novel variants (c.246_250delinsGA and c.1358G>C), four known variants (c.560C>G, c.693C>G, c.982C>T, c.1106G>A), and one known variant (c.644+1G>A). Clinical presentation and disease severity varied across cases, reflecting underlying genotypic heterogeneity. : This study highlights the molecular diversity and clinical variability of iMMA in Malaysia. Our findings reinforce the importance of integrating metabolic screening with molecular diagnostics to identify disease-causing variants and guide patient management strategies effectively. - Source: PubMed
Publication date: 2026/03/03
Masri MardhiahKhalid NorzahidahSalleh NoornatishaLua Seok-HianAbdul Azize Nor AzimahYakob YusnitaAli Ernie ZuraidaMunusamy Vani A/PNgu Lock-HockLee Jeffrey Soon-YitToh Teck-HockHabib Anasufiza - Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal diverse protein activities undergirding this regulation, including MDH2's regulation of MT-ND3 transcription via FASTKD1 binding and CLPP's processing of the mitoribosomal assembly factor MALSU1, which we establish as a disease gene. Through entropy analysis, we reveal unexpectedly heterogeneous protein-level variability across complexes and use complexome profiling to identify new complex-specific membership, including C15orf61's association with complex V. We further observe substantial mtDNA copy number variation, notably upon disruption of the disease-related cobalamin biosynthesis protein MMADHC. Together, we establish new protein functions and provide a multilayered view into mitochondrial proteome regulation. - Source: PubMed
Publication date: 2026/02/09
Forny PatrickForny MerimaSmith Andrew JSung Andrew YLiu KaixianPagliarini David J - Of the ~1100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including the vitamin B chaperone MMADHC and cytosolic B-dependent methionine synthase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B chaperone MMADHC. - Source: PubMed
Publication date: 2025/12/31
Rath Sneha PLi ZhuGuha ArkajitDong FangcongBanerjee RumaMootha Vamsi K - Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs. - Source: PubMed
Publication date: 2025/12/17
Zhang MengZhang XiashiyaoChen YandanLi MengmengDing QingweiZheng LiangZheng JunkeWan JunGuo Bin