MOCOS is molybdenum cofactor sulfurase (EC 2.8.1.9; also called molybdenum cofactor sulfurtransferase, MoCo sulfurase), a cytosolic, pyridoxal-5'-phosphate (PLP)-dependent enzyme of the class-V (NifS-like) cysteine-desulfurase family. It converts the molybdenum cofactor (MoCo) from its dioxo form into the terminal-sulfido (thio) form. The enzyme is a homodimer of two-domain subunits; the N-terminal NifS-like PLP domain abstracts sulfur from L-cysteine via L-cysteine desulfurase activity (yielding L-alanine and an enzyme-bound persulfide), and the C-terminal MOSC/Moco-binding domain receives the mobilized sulfur and transfers it to the bound Mo-molybdopterin. This sulfurated MoCo is specifically required to activate the molybdo-flavoenzymes xanthine dehydrogenase/oxidase (XDH/XO) and aldehyde oxidase (AOX1); the third human molybdoenzyme, sulfite oxidase, uses the non-sulfurated cofactor and does not depend on MOCOS. Loss-of-function variants in MOCOS cause classical xanthinuria type II, an autosomal-recessive disorder with combined XDH and aldehyde oxidase deficiency, marked by xanthine accumulation and urolithiasis, very low uric acid, and inability to convert allopurinol to oxypurinol.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043545 molybdopterin cofactor metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred participation in molybdopterin cofactor metabolism. Correct but a general relative of the specific MoCo biosynthetic/sulfuration role that MOCOS performs. Retained as non-core in favor of the more specific GO:0006777. |
| GO:0008265 molybdenum cofactor sulfurtransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) support for the core catalytic activity of MOCOS. This is the correct, specific molecular function; accepted and treated as core. Directly corroborated by the IDA and IMP annotations from PMID:34356852 and PMID:11302742. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Root-level catalytic activity from InterPro2GO. Not wrong, but far too general given the specific sulfurtransferase activity (GO:0008265) is annotated with experimental evidence. |
| GO:0006777 Mo-molybdopterin cofactor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: UniRule IEA to the specific Mo-molybdopterin cofactor biosynthetic process. Correct and the appropriate specific BP for MOCOS (it produces the mature sulfurated MoCo). Accepted as the core biological process; also supported by the IMP annotation to the same term. |
| GO:0008265 molybdenum cofactor sulfurtransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: UniRule/HAMAP IEA for the core sulfurtransferase (EC 2.8.1.9) activity. Redundant with the experimentally supported IDA/IMP/IBA annotations to the same term but correct; accepted. |
| GO:0016829 lyase activity | IEA GO_REF:0000104 | REMOVE | Summary: Generic lyase activity transferred electronically by UniRule sequence-feature matching. MOCOS is a sulfurtransferase (EC 2.8.1.9): the terminal reaction transfers sulfur to the Mo-molybdopterin cofactor and is not a lyase (non-hydrolytic bond-cleavage) reaction. This is an incorrect electronic over-propagation and is removed. |
| GO:0030151 molybdenum ion binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Molybdenum ion binding by UniRule IEA. MOCOS binds and modifies the Mo-molybdopterin cofactor (its substrate) rather than acquiring a free molybdenum ion for catalysis, and does not itself insert Mo. Defensible at the family level but not the informative core molecular function; kept as non-core. |
| GO:0030170 pyridoxal phosphate binding | IEA GO_REF:0000120 | ACCEPT | Summary: Pyridoxal-5'-phosphate binding. MOCOS is a class-V PLP-dependent (NifS-like) cysteine desulfurase; PLP is covalently bound at Lys264 and is essential for the sulfur-mobilizing step. Directly supported experimentally (PMID:34356852 shows the Thr349Ile variant reduces PLP binding and abolishes desulfurase activity). Accepted as a core catalytic cofactor. |
| GO:0032324 molybdopterin cofactor biosynthetic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA to molybdopterin cofactor biosynthetic process. Correct but a more general relative of the specific GO:0006777 (Mo-molybdopterin cofactor biosynthetic process); kept as non-core. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a high-throughput interactome dataset (interactor PARVA, Q9NVD7). Uninformative for the molecular function of MOCOS and not functionally characterized; marked as over-annotated (IPI retained per policy). |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a proteome-scale interactome map (interactor PARVA, Q9NVD7). Not an informative molecular function; over-annotation (IPI retained per policy). |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from an interactome community-architecture study (interactor PARVA, Q9NVD7). Uninformative for function; over-annotation (IPI retained per policy). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a binary (Y2H) interactome reference map (interactor ARL8A, Q96BM9). Not functionally informative for MoCo sulfuration; over-annotation (IPI retained per policy). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a proteome-scale interactome study (interactors PARVA/Q9NVD7 and ARL8A/Q96BM9). Uninformative molecular function; over-annotation (IPI retained per policy). |
| GO:0032324 molybdopterin cofactor biosynthetic process | TAS Reactome:R-HSA-947581 | KEEP AS NON CORE | Summary: Reactome TAS to molybdopterin cofactor biosynthetic process (MoCo biosynthesis pathway). Correct but a general relative of the specific GO:0006777; kept as non-core. |
| GO:0008265 molybdenum cofactor sulfurtransferase activity | TAS Reactome:R-HSA-947499 | ACCEPT | Summary: Reactome TAS for the MoCo oxygen-to-sulfur exchange reaction, the core sulfurtransferase activity of MOCOS. Accepted; corroborates the experimental annotations to this term. |
| GO:0006777 Mo-molybdopterin cofactor biosynthetic process | IMP PMID:11302742 Mutation of human molybdenum cofactor sulfurase gene is resp... | ACCEPT | Summary: IMP from the original disease study (Ichida et al. 2001): a loss-of-function HMCS/MOCOS variant causes combined XDH and aldehyde oxidase deficiency, demonstrating the role of MOCOS in producing the mature (sulfurated) molybdenum cofactor. Accepted as the core biological process. |
| GO:0008265 molybdenum cofactor sulfurtransferase activity | IDA PMID:34356852 Classical Xanthinuria in Nine Israeli Families and Two Isola... | ACCEPT | Summary: Direct assay (IDA) evidence: recombinant MOCOS NifS-like domain has PLP-dependent L-cysteine desulfurase activity that supplies sulfur to the Moco, and the pathogenic Thr349Ile variant abolishes this activity. This is the strongest evidence for the core catalytic function; accepted as core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-947499 | ACCEPT | Summary: Cytosolic localization (Reactome TAS), consistent with MoCo biosynthesis and MoCo sulfuration occurring in the cytosol in humans. Accepted as the core cellular location. |
| GO:0008265 molybdenum cofactor sulfurtransferase activity | IMP PMID:11302742 Mutation of human molybdenum cofactor sulfurase gene is resp... | ACCEPT | Summary: IMP for the sulfurtransferase activity from the original disease characterization: a MOCOS/HMCS loss-of-function variant abolishes production of sulfurated MoCo, causing dual XDH/AO deficiency. Accepted; independent experimental support for the core molecular function. |
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