ALDH6A1 encodes methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase [acylating] (MMSDH, EC 1.2.1.27), a mitochondrial-matrix, NAD+- and CoA-dependent member of the aldehyde dehydrogenase (ALDH) superfamily. Unlike most ALDHs, MMSDH is acylating: it couples NAD+-dependent oxidative decarboxylation of its semialdehyde substrate to formation of a CoA thioester. The enzyme catalyzes the shared distal step of valine catabolism and of the beta-alanine/thymine catabolic route. It oxidatively decarboxylates methylmalonate semialdehyde (both (R)- and (S)-enantiomers, derived from valine via 3-hydroxyisobutyrate and from thymine via 3-aminoisobutyrate) to propionyl-CoA, and malonate semialdehyde (from the beta-alanine branch of uracil/cytidine catabolism) to acetyl-CoA, releasing bicarbonate and NADH. It is synthesized with an N-terminal mitochondrial transit peptide (residues 1-33) and assembles as a homotetramer; the catalytic nucleophile is Cys317 and it binds NAD+ through a canonical Rossmann-like site. ALDH6A1 is most highly expressed in kidney and liver. Loss-of-function variants cause the rare autosomal-recessive methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD), presenting with variable methylmalonic/3-hydroxyisobutyric aciduria, elevated beta-alanine and aminoisobutyric acid, developmental delay, and dysmyelination.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004491 methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core catalytic molecular function of ALDH6A1/MMSDH, inferred by phylogeny from an orthologous group (rat, mouse, human, plant) with experimentally verified MMSDH activity. Fully consistent with the UniProt catalytic-activity block and the human IMP annotation (PMID:23835272). Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt Reaction=2-methyl-3-oxopropanoate + NAD(+) + CoA + H2O = propanoyl-CoA |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Correct compartment inferred by phylogeny. MMSDH carries an N-terminal mitochondrial transit peptide and acts in the mitochondrial matrix. Accurate but less specific than the mitochondrial matrix (GO:0005759) annotation; retained. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0006574 L-valine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. MMSDH catalyzes the distal oxidative-decarboxylation step of valine catabolism, converting valine-derived methylmalonate semialdehyde to propionyl-CoA. Phylogenetic inference corroborated by human IMP (PMID:23835272). Supporting Evidence: PMID:23835272 MMSDH deficiency is an extremely rare, autosomal recessive disorder of valine and thymine metabolism |
| GO:0006210 thymine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. Thymine catabolism yields 3-aminoisobutyrate, deaminated to (R)-methylmalonate semialdehyde, which MMSDH oxidatively decarboxylates. Phylogenetic inference corroborated by human IMP (PMID:23835272). Supporting Evidence: PMID:23835272 Thymine metabolism generates (R)-aminoisobutyric acid (AIBA), which is then deaminated to (R)-methylmalonic semialdehyde |
| GO:0004491 methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Same core catalytic activity as the IBA/IMP annotations, here derived electronically from InterPro/RHEA/EC:1.2.1.27 mappings. Correct; redundant with the experimental annotation. Kept as non-core supporting evidence for the core MF. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt EC=1.2.1.27 |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Correct localization mapped electronically from the UniProt Subcellular Location vocabulary (SL-0173 Mitochondrion). Accurate but less specific than mitochondrial matrix; retained. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: An InterPro2GO electronic annotation to the broad oxidoreductase root. It is not wrong (MMSDH is an NAD-dependent oxidoreductase) but is far too general given the specific and well-supported GO:0004491 activity is already annotated. Over-annotation by generality; the specific MF should be used instead. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt Reaction=2-methyl-3-oxopropanoate + NAD(+) + CoA + H2O = propanoyl-CoA |
| GO:0009083 branched-chain amino acid catabolic process | TAS Reactome:R-HSA-70895 | KEEP AS NON CORE | Summary: Valine catabolism is a branch of branched-chain amino acid catabolism, so this broader parent process is correct. It is less specific than the L-valine catabolic process annotation but is a valid, author-asserted Reactome pathway membership. Kept as a valid non-core generalization. Supporting Evidence: Reactome:R-HSA-70895 The branched-chain amino acids, leucine, isoleucine, and valine, are all essential amino acids |
| GO:0004491 methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity | TAS Reactome:R-HSA-70893 | ACCEPT | Summary: Core catalytic activity, author-asserted by Reactome for the reaction methylmalonate semialdehyde + NAD+ + CoA + H2O => propionyl-CoA + HCO3- + NADH + H+. Consistent with the experimental IMP annotation. Supporting Evidence: Reactome:R-HSA-70893 Mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1) catalyzes the reaction of methylmalonate semialdehyde, NAD+, and CoA to form propionyl-CoA |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence localization (Human Protein Atlas) placing ALDH6A1 in mitochondria. Experimental confirmation of the mitochondrial localization; accurate but less specific than the matrix annotation. Accepted. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0004491 methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core catalytic activity transferred by sequence similarity from the rat ortholog (UniProtKB:Q02253). Correct and consistent with the human experimental evidence; redundant with the IMP/IBA/TAS annotations of the same term. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt Malonate-semialdehyde dehydrogenase [acylating] {ECO:0000250|UniProtKB:Q02253} |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial-proteome study confirming ALDH6A1 as a mitochondrial protein. Consistent with all other localization evidence; less specific than the matrix annotation. Accepted. Supporting Evidence: file:human/ALDH6A1/ALDH6A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: From a proteome-wide mRNA-interactome capture screen in HeLa cells that cross-linked and recovered ~860 candidate RNA-binding proteins, many of them metabolic enzymes. MMSDH is a mitochondrial ALDH-family catabolic enzyme with no established RNA-regulatory or moonlighting role; this is the classic "intermediary metabolism enzyme caught in interactome capture" pattern, not evidence of a physiological RNA-binding function. High-throughput experimental evidence, so it is not removed, but marked as an over-annotation. Supporting Evidence: PMID:22658674 shedding light on RBPs in disease, RNA-binding enzymes of intermediary metabolism |
| GO:0004491 methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity | IMP PMID:23835272 Mutations in ALDH6A1 encoding methylmalonate semialdehyde de... | ACCEPT | Summary: Strongest, human-specific evidence for the core catalytic activity. In a patient with biallelic ALDH6A1 mutations, MMSDH enzyme activity was directly measured and found markedly reduced in fibroblasts (36 pmol/min/mg vs normal mean 117), linking ALDH6A1 genotype to methylmalonate-semialdehyde dehydrogenase activity. Core molecular function. Supporting Evidence: PMID:23835272 Subsequent MMSDH enzyme assay demonstrated reduced activity |
| GO:0006210 thymine catabolic process | IMP PMID:23835272 Mutations in ALDH6A1 encoding methylmalonate semialdehyde de... | ACCEPT | Summary: Core biological process, supported experimentally. Patients with MMSDH deficiency accumulate thymine-catabolism intermediates (3-aminoisobutyrate/beta-alanine), and the paper explicitly frames the disorder as one of valine and thymine metabolism. Accepted. Supporting Evidence: PMID:23835272 MMSDH deficiency is an extremely rare, autosomal recessive disorder of valine and thymine metabolism |
| GO:0006574 L-valine catabolic process | IMP PMID:23835272 Mutations in ALDH6A1 encoding methylmalonate semialdehyde de... | ACCEPT | Summary: Core biological process, supported experimentally. Loss of MMSDH activity in patients disrupts the valine catabolic route, with accumulation of the valine-derived intermediate 3-hydroxyisobutyrate and methylmalonic acid. Accepted. Supporting Evidence: PMID:23835272 Metabolism of valine produces the intermediate (S)-3-hydroxyisobutyric acid (HIBA), which is oxidized to (S)-methylmalonic semialdehyde |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70893 | ACCEPT | Summary: Most specific and correct localization. As a matrix-soluble enzyme cleaved of its transit peptide, MMSDH acts in the mitochondrial matrix. Core cellular component; preferred over the plainer mitochondrion annotations. Supporting Evidence: Reactome:R-HSA-70893 Mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1) catalyzes the reaction of methylmalonate semialdehyde, NAD+, and CoA to form propionyl-CoA |
| GO:0005739 mitochondrion | NAS PMID:1527093 CoA-dependent methylmalonate-semialdehyde dehydrogenase, a u... | ACCEPT | Summary: Non-traceable author statement from the original cDNA-cloning paper, which characterized the N-terminal mitochondrial targeting peptide. Correct compartment but less specific than the matrix annotation and weaker evidence. Accepted as a valid parent localization. Supporting Evidence: PMID:1527093 the sequence of the 32 amino acids corresponding to the |
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