SLC25A26

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the core SAM transmembrane transporter activity, propagated across the SAM-carrier orthology group (including yeast SAM5 and worm orthologs in the with/from). This is the correct core molecular function and is directly supported by human experimental data.
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the site of action to the mitochondrial inner membrane. Correct core localization for a mitochondrial carrier and corroborated by human IDA evidence and UniProt.
GO:0005739 mitochondrion	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Electronic (ARBA) mitochondrion assignment. Correct but less specific than the mitochondrial inner membrane localization; keep as non-core supporting evidence.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic assignment from the UniProt Subcellular Location keyword mapping (SL-0168). Consistent with the experimentally supported inner-membrane localization.
GO:0015860 purine nucleoside transmembrane transport	IEA GO_REF:0000108	REMOVE	Summary: Inter-ontology logical-inference (GO_REF:0000108, with/from GO:0180003) that SAM/SAH transport implies purine nucleoside transport. This is an artifact of the substrate structure. SAM and SAH contain an adenosyl (purine nucleoside) moiety, but SAMC does not transport free purine nucleosides; its substrates are SAM and SAH. This is a clearly-wrong electronic inference.
GO:1902475 L-alpha-amino acid transmembrane transport	IEA GO_REF:0000108	REMOVE	Summary: Inter-ontology logical-inference (GO_REF:0000108, with/from GO:0180003) that SAM/SAH transport implies L-alpha-amino acid transport. SAM and SAH derive from methionine/homocysteine and carry an amino-acid moiety, but SAMC does not transport free L-amino acids. This is a clearly-wrong electronic inference.
GO:0015837 amine transport	TAS Reactome:R-HSA-549127	MARK AS OVER ANNOTATED	Summary: The cited Reactome pathway R-HSA-549127 is "SLC-mediated transport of organic cations" (SLC22/OCT family, ergothioneine and carnitine transport), not the SAMC AdoMet/AdoHcy exchange (which is Reactome R-HSA-8855062). "amine transport" mischaracterizes the substrate; SAM is a sulfonium metabolite transported by antiport with SAH, not a generic amine. This is an over-annotation via a mismatched pathway grouping.
GO:0005739 mitochondrion	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence (IDA) localizing SAMC to mitochondria. Correct but less specific than the inner-membrane localization; keep as non-core supporting evidence.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput detection of SAMC (Q70HW3) in a quantitative human mitochondrial proteome dataset. Consistent with mitochondrial localization but less specific than the inner-membrane assignment; keep as non-core supporting evidence.
GO:0180003 S-adenosyl-L-methionine:S-adenosyl-L-homocysteine antiporter activity	IMP PMID:26522469 Intra-mitochondrial Methylation Deficiency Due to Mutations ...	ACCEPT	Summary: Reconstituted-liposome transport assays on COXPD28 disease variants demonstrated loss of SAM transport capacity, supporting the specific SAM:SAH antiporter (countertransport) mechanism. This is the precise molecular function of SAMC. Supporting Evidence: PMID:26522469 demonstrated a severe abrogation of SAM transport capacity for all altered proteins
GO:0180003 S-adenosyl-L-methionine:S-adenosyl-L-homocysteine antiporter activity	IMP PMID:34375635 Identification and characterization of novel compound varian...	ACCEPT	Summary: Case report characterizing novel compound-heterozygous SLC25A26 variants (A12P, A66E) in a COXPD28 patient, corroborating SAMC's role as the mitochondrial SAM carrier. Supports the antiporter activity term; the mechanistic assignment is more directly established by the reconstitution studies (PMID:14674884, PMID:26522469). Supporting Evidence: PMID:34375635 the mitochondrial S-adenosylmethionine carrier (SAMC) that responsible for the transport of S-adenosylmethionine (SAM) into the mitochondria
GO:0180003 S-adenosyl-L-methionine:S-adenosyl-L-homocysteine antiporter activity	EXP PMID:14674884 Identification of the human mitochondrial S-adenosylmethioni...	ACCEPT	Summary: Foundational experimental characterization. Purified recombinant SAMC reconstituted into liposomes was identified by its transport properties as the human mitochondrial SAM carrier, catalysing essentially only countertransport (antiport). This is the primary evidence for the SAM:SAH antiporter activity. Supporting Evidence: PMID:14674884 SAMC catalysed virtually only countertransport, exhibited a higher transport affinity for SAM
GO:0180003 S-adenosyl-L-methionine:S-adenosyl-L-homocysteine antiporter activity	EXP PMID:35024855 Pathogenic SLC25A26 variants impair SAH transport activity c...	ACCEPT	Summary: Functional studies in Slc25a26-null MEF and Drosophila models showed that adult-onset disease variants selectively impair the SAH limb of the antiport, directly supporting the SAM:SAH antiporter mechanism (both substrate limbs are properties of the same carrier). Supporting Evidence: PMID:35024855 impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely the cause of this milder, late-onset phenotype
GO:0043414 macromolecule methylation	IMP PMID:26522469 Intra-mitochondrial Methylation Deficiency Due to Mutations ...	KEEP AS NON CORE	Summary: SAMC is a transporter, not a methyltransferase; loss of SAM import reduces intramitochondrial methylation of RNA and proteins. The acts_upstream_of qualifier correctly captures this indirect, downstream relationship. Keep as non-core (the direct molecular function is transport, not methylation). Supporting Evidence: PMID:26522469 impaired SAM transport into mitochondria causes a complex syndrome causing multiple primary defects, including those affecting RNA stability, protein modification
GO:1990543 mitochondrial S-adenosyl-L-methionine transmembrane transport	IMP PMID:26522469 Intra-mitochondrial Methylation Deficiency Due to Mutations ...	ACCEPT	Summary: Disease-variant reconstitution assays showing abrogated SAM transport support the specific process of mitochondrial SAM transmembrane transport. This is the core biological process for SAMC. Supporting Evidence: PMID:26522469 demonstrated a severe abrogation of SAM transport capacity for all altered proteins
GO:1990543 mitochondrial S-adenosyl-L-methionine transmembrane transport	IMP PMID:34375635 Identification and characterization of novel compound varian...	ACCEPT	Summary: Case report of COXPD28 compound-heterozygous variants supporting SAMC's role in transporting SAM into mitochondria. Consistent with the core mitochondrial SAM transport process. Supporting Evidence: PMID:34375635 the mitochondrial S-adenosylmethionine carrier (SAMC) that responsible for the transport of S-adenosylmethionine (SAM) into the mitochondria
GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity	EXP PMID:14674884 Identification of the human mitochondrial S-adenosylmethioni...	ACCEPT	Summary: Foundational experimental identification of SAMC as the human mitochondrial SAM transporter by functional reconstitution of the purified protein in liposomes. This is the primary evidence for the core SAM transmembrane transporter activity. Supporting Evidence: PMID:14674884 identified from its transport properties as the human mitochondrial SAM carrier (SAMC)
GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity	EXP PMID:26522469 Intra-mitochondrial Methylation Deficiency Due to Mutations ...	ACCEPT	Summary: Disease-variant reconstitution assays confirm the SAM transmembrane transporter activity of SAMC. Core molecular function. Supporting Evidence: PMID:26522469 demonstrated a severe abrogation of SAM transport capacity for all altered proteins
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-8855062	ACCEPT	Summary: Reactome traceable assertion (R-HSA-8855062, "SLC25A26 exchanges cytosolic AdoMet for mitochondrial AdoHcy") placing SAMC at the inner mitochondrial membrane. Correct core localization, consistent with experimental IDA evidence.
GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity	IMP PMID:14674884 Identification of the human mitochondrial S-adenosylmethioni...	ACCEPT	Summary: UniProt IMP assignment of SAM transmembrane transporter activity from the Agrimi et al. functional characterization. Redundant with the EXP annotations but correct; core molecular function. Supporting Evidence: PMID:14674884 identified from its transport properties as the human mitochondrial SAM carrier (SAMC)
GO:0005743 mitochondrial inner membrane	IDA PMID:14674884 Identification of the human mitochondrial S-adenosylmethioni...	ACCEPT	Summary: Direct experimental localization of SAMC to mitochondria (the inner membrane being the site of mitochondrial carriers). This is the strongest evidence for the core inner-membrane localization. Supporting Evidence: PMID:14674884 was localized to the mitochondria
GO:0015805 S-adenosyl-L-methionine transport	IMP PMID:14674884 Identification of the human mitochondrial S-adenosylmethioni...	KEEP AS NON CORE	Summary: General SAM transport process, experimentally supported by the Agrimi et al. reconstitution. Correct, but the mitochondrion-specific child term GO:1990543 (mitochondrial SAM transmembrane transport) more precisely captures SAMC's biological role; keep this parent term as non-core. Supporting Evidence: PMID:14674884 identified from its transport properties as the human mitochondrial SAM carrier (SAMC)

Gene Description

Existing Annotations Review

Core Functions

Imports cytosolic S-adenosyl-L-methionine (SAM) into the mitochondrial matrix in antiport exchange for S-adenosylhomocysteine (SAH), acting as the SAM:SAH antiporter of the mitochondrial inner membrane. This supplies SAM as the methyl donor for matrix methyltransferases.

Transports S-adenosyl-L-methionine across the mitochondrial inner membrane; SAMC is the only known route for SAM entry into mitochondria.

References

📚 Additional Documentation

Notes

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