UniProt: Q70HW3 (SAMC_HUMAN). HGNC:20661. Gene: SLC25A26. Synonym: SAMC.
274 aa, mitochondrial carrier (TC 2.A.29) family, 6 predicted TM helices, 3 Solcar repeats.
SLC25A26 encodes the mitochondrial S-adenosyl-L-methionine carrier (SAMC), the only
known transporter that imports S-adenosylmethionine (SAM/AdoMet) into the mitochondrial
matrix. It is a multi-pass inner-membrane antiporter that exchanges cytosolic SAM for
matrix S-adenosylhomocysteine (SAH/AdoHcy), the by-product of intramitochondrial
methylation reactions. Imported SAM is the methyl donor for matrix methyltransferases
acting on mtDNA/mt-RNA, proteins, and cofactor biosynthesis (lipoic acid, coenzyme Q10).
Agrimi et al. 2004 PMID:14674884 identified and biochemically characterized human SAMC:
the cDNA was overexpressed in bacteria, the purified protein reconstituted into liposomes,
and its transport properties established it as the human mitochondrial SAM carrier. Key
findings (abstract; full text not in cache):
- "SAM (S-adenosylmethionine) has to be transported into the mitochondria where it is
converted into S-adenosylhomocysteine in methylation reactions of DNA, RNA and proteins."
- "its product was purified, reconstituted into phospholipid vesicles and identified from
its transport properties as the human mitochondrial SAM carrier (SAMC)."
- "Unlike the yeast orthologue, SAMC catalysed virtually only countertransport, exhibited a
higher transport affinity for SAM and was strongly inhibited by tannic acid and Bromocresol
Purple."
- "SAMC was found to be expressed in all human tissues examined and was localized to the
mitochondria."
- "The physiological role of SAMC is probably to exchange cytosolic SAM for mitochondrial
S-adenosylhomocysteine."
[PMID:14674884 abstract]
This paper is the experimental basis (EXP/IMP by UniProt and Reactome) for MF terms
GO:0000095 (SAM transmembrane transporter activity), GO:0180003 (SAM:SAH antiporter
activity), and BP terms GO:0015805 / GO:1990543 (SAM transport / mitochondrial SAM
transmembrane transport).
Kishita et al. 2015 PMID:26522469 — COXPD28; full text available. Three families with
recessive SLC25A26 mutations; the paper both re-establishes the transporter function and
demonstrates the downstream methylation consequences:
- "The human mitochondrial SAM carrier (SAMC), encoded by SLC25A26 (MIM: 611037), is
expressed in all human tissues examined and is believed to be the only route of SAM entry
into mitochondria." [PMID:26522469 full text]
- Reconstituted-liposome SAM transport assays on COXPD28 variants (A102V, V148G, P199L) and
a SAMCΔ1–88 splice product: "demonstrated a severe abrogation of SAM transport capacity for
all altered proteins ... SAMCΔ1–88 was completely inactive, whereas p.Ala102Val and
p.Pro199Leu variants exhibited negligible activity, and p.Val148Gly strongly inhibited SAMC
activity (15% of wild-type SAMC)." [PMID:26522469 full text] — supports GO:0000095 /
GO:0180003 (IMP) and GO:1990543 (IMP).
- Downstream methylation defects: 12S rRNA adenine dimethylation reduced; protein methylation
(ANT1/ANT2, ETFB) reduced; lipoic acid (PDHC-E2, α-KGDH-E2) and CoQ10 reduced.
"impaired SAM transport into mitochondria causes a complex syndrome causing multiple primary
defects, including those affecting RNA stability, protein modification, mitochondrial
translation, and the biosynthesis of CoQ10 and LA." [PMID:26522469 full text] — supports
GO:0043414 macromolecule methylation (acts_upstream_of, IMP).
Schober/Rosenberger et al. 2022 PMID:35024855 — full text available. Two adult-onset
COXPD28 cases (variants R142Q, E135G). Establishes that these milder variants impair the SAH
limb of the antiport rather than SAM import:
- "The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports
S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for
S-adenosylhomocysteine (SAH)." PMID:35024855
- "SAMC is the only entry route for SAM into the mitochondrial matrix." PMID:35024855
- "impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely
the cause of this milder, late-onset phenotype." PMID:35024855 — supports GO:0180003
(antiporter activity, EXP): both SAM and SAH limbs are functional properties of the same
antiporter.
Ji et al. 2021 PMID:34375635 — case report, novel compound-het variants (A12P, A66E) in a
Chinese COXPD28 patient; abstract only. Corroborates SAMC as "the mitochondrial
S-adenosylmethionine carrier (SAMC) that responsible for the transport of
S-adenosylmethionine (SAM) into the mitochondria." Note: this paper reports/analyzes variants
in silico and by structural modeling; used by UniProt as IMP for GO:0180003 and GO:1990543.
Core molecular functions:
- GO:0000095 S-adenosyl-L-methionine transmembrane transporter activity — CORE MF (EXP/IMP).
- GO:0180003 SAM:SAH antiporter activity — CORE MF, the specific mechanism (EXP/IMP; both SAM
and SAH limbs experimentally supported).
Core cellular component:
- GO:0005743 mitochondrial inner membrane — CORE (IDA, PMID:14674884; also IBA is_active_in).
Core biological process:
- GO:1990543 mitochondrial S-adenosyl-L-methionine transmembrane transport — CORE (IMP).
- GO:0015805 S-adenosyl-L-methionine transport — parent/general form of the above; ACCEPT but
the mitochondrial-specific 1990543 is the better term.
Non-core / supporting:
- GO:0005739 mitochondrion (IEA/IDA/HTP) — correct but less specific than 0005743; keep,
non-core.
- GO:0043414 macromolecule methylation, acts_upstream_of (IMP) — indirect/downstream effect;
SAMC is a transporter, not a methyltransferase. Keep as non-core (acts_upstream_of correctly
captures the indirect relationship).
Over-annotations / removals:
- GO:0015860 purine nucleoside transmembrane transport (IEA, GO_REF:0000108, with/from
GO:0180003) — logical-inference artifact: SAM/SAH contain an adenosyl (purine nucleoside)
moiety, but SAMC does not transport free purine nucleosides. Clearly-wrong IEA → REMOVE.
- GO:1902475 L-alpha-amino acid transmembrane transport (IEA, GO_REF:0000108, with/from
GO:0180003) — same artifact: SAM/SAH contain a methionine/homocysteine-derived amino-acid
moiety, but SAMC does not transport free L-amino acids. Clearly-wrong IEA → REMOVE.
- GO:0015837 amine transport (TAS, Reactome:R-HSA-549127) — the Reactome pathway
R-HSA-549127 is "SLC-mediated transport of organic cations" (OCT/SLC22 family, ergothioneine,
carnitine), NOT the SAMC AdoMet/AdoHcy reaction (which is R-HSA-8855062). "amine transport"
is a mischaracterization of SAMC's substrate (SAM is a sulfonium metabolite, not transported
as a generic amine). Over-annotation via a mismatched Reactome pathway → MARK_AS_OVER_ANNOTATED
(TAS, do not REMOVE experimental/authored assertions per policy; flag as over-annotated).