MOCS1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0061798 GTP 3',8'-cyclase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of the MOCS1A activity (GTP 3',8-cyclase, EC 4.1.99.22). This is a core molecular function of MOCS1 and is directly supported by experimental annotations (EXP, PMID:31996372) and by UniProt catalytic-activity records. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt MOCS1A catalyzes the cyclization of
GO:0061799 cyclic pyranopterin monophosphate synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of the MOCS1B activity (cyclic pyranopterin monophosphate synthase, EC 4.6.1.17). Core molecular function, directly supported by experimental annotations (EXP PMID:23627491; IGI/IMP). Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt MOCS1B
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of the pathway MOCS1 initiates. This is the core biological process and is strongly supported by experimental and patient-mutation (IMP/IDA) annotations.
GO:0003824 catalytic activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Root-level "catalytic activity" from InterPro2GO. MOCS1 is an enzyme, so this is not wrong, but it is an uninformative parent that is fully subsumed by the specific GTP 3',8-cyclase (GO:0061798) and cyclic pyranopterin monophosphate synthase (GO:0061799) annotations. Over-annotation.
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Cytoplasm from UniProt subcellular-location mapping. Consistent with the cytosolic N-terminal splice variants (e.g. isoform 2/3) and the pre-import pool, but the core catalytic site is the mitochondrial matrix. General term; kept as non-core. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm, cytosol
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: Mitochondrial matrix from UniProt subcellular-location mapping. This is the core site of MOCS1A/MOCS1B catalysis and is experimentally supported (IDA, PMID:31996372). Accept. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt SUBCELLULAR LOCATION: [Isoform MOCS1A]: Mitochondrion matrix
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Cytosol from UniProt subcellular-location mapping. Reflects the cytosolic splice variants (isoform 2 = cytosol); the mature catalytic proteins act in the mitochondrial matrix. Kept as non-core. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm, cytosol
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO inference of the core Moco biosynthetic process. Redundant with the experimental/IBA annotations to the same term. Accept as core.
GO:0032324 molybdopterin cofactor biosynthetic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA (machine-learning) inference to a broader/legacy sibling of GO:0006777. Not wrong, but redundant with the more specific Mo-molybdopterin cofactor biosynthetic process (GO:0006777). Kept as non-core.
GO:0046872 metal ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Generic "metal ion binding" from InterPro2GO. MOCS1A binds iron via its [4Fe-4S] clusters, so this is not wrong, but it is an uninformative parent of the specific 4Fe-4S cluster binding (GO:0051539). Kept as non-core.
GO:0051536 iron-sulfur cluster binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Iron-sulfur cluster binding from InterPro2GO. Correct but a direct parent of the more specific 4 iron, 4 sulfur cluster binding (GO:0051539), which is experimentally characterized. Kept as non-core.
GO:0051539 4 iron, 4 sulfur cluster binding	IEA GO_REF:0000002	ACCEPT	Summary: 4Fe-4S cluster binding from InterPro2GO. MOCS1A is a radical-SAM enzyme that binds two [4Fe-4S] clusters; this is experimentally characterized (PMID:15180982). Core supporting molecular function. Accept. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt Binds 2 [4Fe-4S] clusters. PMID:15180982 yield a form containing
GO:0061798 GTP 3',8'-cyclase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (EC/Rhea-based) inference of the MOCS1A GTP 3',8-cyclase activity. Consistent with the experimental EXP annotation to the same term. Accept as core.
GO:0061799 cyclic pyranopterin monophosphate synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (EC/Rhea-based) inference of the MOCS1B cPMP synthase activity. Consistent with the experimental EXP annotation to the same term. Accept as core.
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence localizing MOCS1 to the cytosol. Consistent with the cytosolic splice variants and pre-import pool; the mature catalytic proteins act in the mitochondrial matrix. Experimental localization retained as non-core relative to the matrix site of catalysis.
GO:0005737 cytoplasm	EXP PMID:31996372 Alternative splicing of the bicistronic gene molybdenum cofa...	KEEP AS NON CORE	Summary: Experimental (fluorescence microscopy/cell fractionation) localization. PMID:31996372 showed that some N-terminal (exon 1b) MOCS1A splice variants remain cytosolic while others (exon 1a) go to the mitochondrial matrix. Cytoplasm is correct for the cytosolic variants but the core catalytic pool is the mitochondrial matrix; kept as non-core. Supporting Evidence: PMID:31996372 either localize
GO:0061798 GTP 3',8'-cyclase activity	EXP PMID:31996372 Alternative splicing of the bicistronic gene molybdenum cofa...	ACCEPT	Summary: Experimental support for the MOCS1A GTP 3',8-cyclase activity (EC 4.1.99.22). PMID:31996372 assayed catalytic activity of MOCS1A splice isoforms; UniProt cites this paper for the EC 4.1.99.22 reaction. Core molecular function. Accept. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt EC=4.1.99.22 {ECO:0000269\|PubMed:31996372}
GO:0061799 cyclic pyranopterin monophosphate synthase activity	EXP PMID:23627491 Identification of a cyclic nucleotide as a cryptic intermedi...	ACCEPT	Summary: Experimental support for the MOCS1B cyclic pyranopterin monophosphate synthase activity (EC 4.6.1.17). PMID:23627491 directly assayed the human homolog MOCS1B, showing it converts 3',8-cH2GTP to cPMP (Km 0.79 uM). Core molecular function. Accept. Supporting Evidence: PMID:23627491 its human homologue, MOCS1B, with
GO:0005759 mitochondrial matrix	IDA PMID:31996372 Alternative splicing of the bicistronic gene molybdenum cofa...	ACCEPT	Summary: Direct experimental localization of the mature MOCS1A/MOCS1B proteins to the mitochondrial matrix (is_active_in). PMID:31996372 showed MOCS1AB is proteolytically cleaved within mitochondria to give matrix-localized MOCS1B. This is the core site of cPMP biosynthesis. Accept. Supporting Evidence: PMID:31996372 mitochondrial matrix localization of the MOCS1B domain.
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IDA PMID:15180982 Characterization of MOCS1A, an oxygen-sensitive iron-sulfur ...	ACCEPT	Summary: Direct experimental support for MOCS1 involvement in Moco biosynthesis. PMID:15180982 characterized MOCS1A as the oxygen-sensitive Fe-S radical-SAM enzyme catalyzing the first step; the conserved cysteines are essential for precursor-Z synthesis in vivo. Core biological process. Accept. Supporting Evidence: PMID:15180982 essential for synthesis of
GO:0061799 cyclic pyranopterin monophosphate synthase activity	IMP PMID:15180982 Characterization of MOCS1A, an oxygen-sensitive iron-sulfur ...	ACCEPT	Summary: Mutational (IMP) support that MOCS1 activity generating precursor Z depends on the conserved MOCS1A cysteines; associated in GOA with the cPMP synthase (MOCS1B) step of the same GTP-to-cPMP conversion. Core molecular function of MOCS1. Accept. Supporting Evidence: PMID:15180982 essential for synthesis of
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IMP PMID:29368224 A mild case of molybdenum cofactor deficiency defines an alt...	ACCEPT	Summary: Mutational (IMP) support from a mild MoCD patient (c.1338delG). PMID:29368224 showed the truncation removes MOCS1B, and residual MOCS1B from translation re-initiation partially rescues Moco synthesis. Core biological process. Accept. Supporting Evidence: PMID:29368224 confirmed activity of MOCS1B, but not of the
GO:0061799 cyclic pyranopterin monophosphate synthase activity	IGI PMID:29368224 A mild case of molybdenum cofactor deficiency defines an alt...	ACCEPT	Summary: Genetic-interaction (IGI, with E. coli MoaC UniProtKB:P0A738) support for the MOCS1B cPMP synthase activity. PMID:29368224 functionally confirmed activity of the residual MOCS1B protein. Core molecular function. Accept. Supporting Evidence: PMID:29368224 confirmed activity of MOCS1B, but not of the
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput mitochondrial-proteome detection (PMID:34800366) placing MOCS1 in the mitochondrion. Consistent with the experimentally established mitochondrial matrix localization but a general term from a proteome-wide screen. Kept as non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-947535	KEEP AS NON CORE	Summary: Reactome (TAS) places the GTP-to-precursor-Z reaction in the cytosol. This predates the demonstration (PMID:31996372) that the mature catalytic MOCS1A/MOCS1B proteins act in the mitochondrial matrix; consistent with the cytosolic splice variants. Kept as non-core.
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	TAS PMID:12754701 Mutations in the molybdenum cofactor biosynthetic genes MOCS...	ACCEPT	Summary: Traceable author statement (review, PMID:12754701) that MOCS1 encodes the first enzymes of Moco biosynthesis. Core biological process. Accept. Supporting Evidence: PMID:12754701 results primarily from the
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IMP PMID:16021469 Ten novel mutations in the molybdenum cofactor genes MOCS1 a...	ACCEPT	Summary: Mutational (IMP) support from disease-mutation analysis (PMID:16021469) confirming MOCS1 involvement in Moco biosynthesis. Core biological process. Accept. Supporting Evidence: PMID:16021469 result in a lethal
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IMP PMID:9731530 Mutations in a polycistronic nuclear gene associated with mo...	ACCEPT	Summary: Mutational (IMP) support from the original disease-gene identification (PMID:9731530): mutations in both MOCS1 ORFs (moaA/moaC homologs) confirm their functional role in Moco synthesis. Core biological process. Accept. Supporting Evidence: PMID:9731530 confirm the functional role of both ORFs
GO:0006777 Mo-molybdopterin cofactor biosynthetic process	IMP PMID:9921896 Genomic structure and mutational spectrum of the bicistronic...	ACCEPT	Summary: Mutational (IMP) support from genomic/mutational-spectrum analysis (PMID:9921896) confirming MOCS1 as the molybdenum cofactor deficiency type A gene. Core biological process. Accept. Supporting Evidence: PMID:9921896 the first two enzymes
GO:1904047 S-adenosyl-L-methionine binding	IEA GO_REF:0000003	NEW	Summary: MOCS1A is a radical-SAM enzyme that uses S-adenosyl-L-methionine as the radical-generating cosubstrate (UniProt BINDING residues 86 and 127; Ensembl-projected IEA in the UniProt DR block, not present in this GOA snapshot). Included here as a NEW supporting molecular function of MOCS1A. Supporting Evidence: file:human/MOCS1/MOCS1-uniprot.txt /ligand="S-adenosyl-L-methionine" PMID:15180982 S-adenosylmethionine (AdoMet)-dependent radical enzymes

Gene Description

Existing Annotations Review

Core Functions

MOCS1A (N-terminal region) is a radical S-adenosyl-L-methionine enzyme that catalyses the first sub-step of molybdenum cofactor biosynthesis, converting GTP to (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate (GTP 3',8-cyclase, EC 4.1.99.22), using two [4Fe-4S] clusters and SAM.

MOCS1A binds two [4Fe-4S] clusters (one 4Fe-4S-S-AdoMet cluster and one binding the GTP-derived substrate), which are required for the radical-SAM GTP 3',8-cyclase reaction.

MOCS1A uses S-adenosyl-L-methionine as the radical-generating cosubstrate: the [4Fe-4S] cluster reductively cleaves SAM to a 5'-deoxyadenosyl radical that initiates the C-C bond formation converting GTP to the cyclic intermediate.

MOCS1B (C-terminal region, a MoaC-family enzyme) is cyclic pyranopterin monophosphate synthase (EC 4.6.1.17), converting (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate to cyclic pyranopterin monophosphate (cPMP, precursor Z), completing the first step of Moco biosynthesis.

References

📚 Additional Documentation

Notes

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