SULT1A1 (sulfotransferase 1A1; historically thermostable phenol sulfotransferase, TS-PST / P-PST-1 / HAST1 / ST1A3) is a cytosolic, homodimeric sulfotransferase (EC 2.8.2.1) that transfers the sulfonate group of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) onto the hydroxyl group of small acceptor molecules, releasing adenosine 3',5'-bisphosphate. His108 acts as the catalytic base and a conserved PAPS-binding cradle (residues 48-53, 130, 138, 193, 227-232, 255-259) positions the donor; the acceptor pocket is small, hydrophobic and unusually plastic, which gives the enzyme its hallmark broad specificity for simple planar phenols and also produces partial substrate inhibition, because a second acceptor molecule can bind in a catalytically unproductive orientation. It is the dominant sulfotransferase of human liver and is also expressed in gut, lung, adrenal, brain, thyroid, platelets and skin, where it carries out phase II conjugation of drugs and dietary and environmental phenols - acetaminophen, minoxidil, 4-nitrophenol, flavonoids such as hesperetin, and the gut-bacterial metabolite 4-ethylphenol - converting them to water-soluble sulfate esters for excretion. Among the human sulfotransferases that have been compared directly it has the highest affinity for the iodothyronines, sulfating the outer-ring 4'-hydroxyl of 3,3'-T2, reverse T3, T3 and T4 (preference 3,3'-T2 >> rT3 > T3 > T4; Km 0.14 uM for 3,3'-T2, some 240-fold tighter than SULT1A3) and thereby feeding thyroid hormone into the deiodinase-mediated degradation route; SULT1A3 and SULT1B1 sulfate iodothyronines as well. The same chemistry has a toxicological face: sulfonation of N-hydroxy-arylamines and N-hydroxy heterocyclic amines yields unstable esters that decompose to DNA-binding electrophiles, making SULT1A1 a major bioactivator of dietary and environmental procarcinogens. It additionally sulfates 17beta-estradiol, dopamine and ethanol in vitro, but with affinities far below those of the isoforms dedicated to those substrates (SULT1E1 and SULT1A3). The gene is polymorphic and copy-number variable; the common Arg213His allele (SULT1A1*2) lowers both activity and thermostability.
Definition: Catalysis of the reaction: 3'-phosphoadenosine 5'-phosphosulfate + an iodothyronine = adenosine 3',5'-bisphosphate + an iodothyronine sulfate + H+. The sulfonate group is transferred to the phenolic 4'-hydroxyl of the outer ring of thyroid hormones and their metabolites, including L-thyroxine (T4), 3,3',5-triiodo-L-thyronine (T3), 3,3',5'-triiodo-L-thyronine (reverse T3) and 3,3'-diiodo-L-thyronine.
Justification: GO has no molecular function term for iodothyronine sulfation, although it is a principal route of thyroid hormone inactivation and is the highest-affinity chemistry documented for SULT1A1 (Km 0.14 uM for 3,3'-T2, roughly 240-fold tighter than SULT1A3). UniProt curates four distinct iodothyronine RHEA reactions for it on P50225 (RHEA:67876, RHEA:67888, RHEA:67892, RHEA:83575) with ECO:0000269 evidence, and Reactome models three of them (R-HSA-176474, R-HSA-176585). At present curators must fall back on either GO:0008146 sulfotransferase activity, which loses the substrate entirely, or GO:0004062 aryl sulfotransferase activity, which is correct chemically but does not distinguish thyroid hormone from any other phenol. The chemistry is independently replicated rather than resting on a single study. PMID:11739018 measures the same 3,3'-T2 > rT3 > T3 > T4 ordering in a second laboratory using both common allozymes, and extends the series with 3,5-T2 as by far the poorest acceptor. Read across the whole series, that is a structure-activity result about outer-ring iodine substitution rather than about the hydroxyl: counting outer-ring iodines gives 3,3'-T2 (one) > rT3 (two) > T3 (one) > T4 (two, plus two inner) >> 3,5-T2 (none). 3,5-T2 is the only member whose outer ring is un-iodinated, and it is the one the enzyme barely touches, so what SULT1A1 selects for is iodine substitution adjacent to the 4'-hydroxyl. The 4'-regiospecificity written into the definition above is sourced separately and more directly - to the identity of the products themselves (the iodothyronine sulfates are 4'-O-sulfates) and to the UniProt/RHEA reactions already cited - not to this kinetic series. PMID:9848125 separates SULT1A1 from its closest paralog on this chemistry: hydroxylated PCBs inhibit 3,3'-T2 sulfation by hSULT1A1 but not by hSULT1A3. PMID:15531517 shows the activity is measurable in native human thyroid cytosol with the same 3,3'-T2 preference, so the term is not describing a recombinant-only phenomenon. Suggest "thyroid hormone sulfotransferase activity" as an exact synonym rather than the primary label. The substrate-class label is the more accurate of the two because the highest-affinity, preferred acceptors (3,3'-T2 and reverse T3) are inactive thyroid hormone *metabolites* rather than the active hormones, so the physiological centre of this chemistry is terminal clearance of already-degraded iodothyronines rather than regulation of active T3. Generic applicability: the term is reusable beyond SULT1A1. UniProt carries curated iodothyronine reactions for SULT1A3 (P0DMM9, four) and SULT1B1 (O43704, three). An earlier draft of this proposal also listed SULT1E1; that was asserted without checking and is wrong - P49888 has no curated iodothyronine catalytic activity at all (its five curated reactions are estrone, 24S-hydroxycholesterol, 17beta-estradiol, dehydroepiandrosterone and 4-ethylphenol), so SULT1E1 must be verified against primary literature before the term is carried to it. An independent OLS query confirms no existing GO molecular-function term covers this reaction.
Parent term: aryl sulfotransferase activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004062 aryl sulfotransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of the defining catalytic activity of the SULT1 family: PAPS-dependent transfer of a sulfonate group to a phenolic acceptor (EC 2.8.2.1). This is the correct core molecular function for SULT1A1 and is independently established by five EXP and three IDA annotations plus four crystal structures of the human enzyme. Reason: The IBD node behind this IBA is seeded by a large, well-characterized set of vertebrate SULT1 members (mouse, rat, cow, dog, chicken and multiple human paralogs). SULT1A1 sits squarely inside the clade that inherited the activity, retains His108 and the complete PAPS-binding cradle, and has its own direct experimental evidence for the term - which is why P50225 legitimately appears in its own WITH/FROM list, marking descendant-level experimental grounding rather than circularity. Supporting Evidence: PMID:22069470 Cytosolic sulfotransferases (SULTs) are mammalian enzymes that detoxify a wide variety of chemicals through the addition of a sulfate group. file:human/SULT1A1/SULT1A1-uniprot.txt Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine group. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that the SULT1 family acts in the cytoplasm. Correct for SULT1A1: the protein has no signal peptide, transmembrane segment or organellar targeting feature, and its localization is experimentally established. The more precise term cytosol (GO:0005829) is separately annotated from Reactome. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0051923 sulfation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that the family is involved in sulfation. This is the direct biological consequence of the catalytic activity and is the correct core biological process for SULT1A1, independently supported by four IDA annotations. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites. |
| GO:0004062 aryl sulfotransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of the core aryl sulfotransferase activity via combined automated methods, drawing on the curated EC number (EC 2.8.2.1) and six RHEA reactions in the UniProt entry (RHEA:12164 phenol, RHEA:66548 4-nitrophenol, RHEA:67876/67888/67892 iodothyronines, RHEA:83575 L-thyroxine). Each of those reactions carries ECO:0000269 experimental evidence, so this IEA is correct and redundant with the experimental annotations rather than an over-propagation. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt Reaction=a phenol + 3'-phosphoadenylyl sulfate = an aryl sulfate + adenosine 3',5'-bisphosphate + H(+) |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of the UniProt subcellular-location keyword SL-0086 (Cytoplasm), which is itself backed by ECO:0000269|PubMed:8093002. Correct. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006790 sulfur compound metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learned assertion of a very general biological process. Not wrong - sulfation is a child of sulfur compound metabolic process - but it conveys nothing beyond the sulfation term already annotated with IBA and four IDA annotations. Reason: GO:0051923 sulfation is a direct descendant of GO:0006790 and is exactly what SULT1A1 does; the ancestor term adds no information and dilutes the annotation set. Replace with the specific child. Proposed replacements: sulfation Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine group. |
| GO:0008146 sulfotransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of sulfotransferase activity from the InterPro sulfotransferase domain (IPR000863) and an ARBA rule. This is the correct family-level activity; the domain-based method cannot resolve acceptor preference, so the general term is method-appropriate here, and the specific child GO:0004062 is separately annotated. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt SIMILARITY: Belongs to the sulfotransferase 1 family. |
| GO:0050294 steroid sulfotransferase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: RHEA-based electronic annotation derived from RHEA:52372 (17beta-estradiol + PAPS = 17beta-estradiol 3-sulfate + PAP + H+), which carries ECO:0000269 evidence from PubMed:16221673. The activity is genuine, but it is a low-affinity side reaction of the small-phenol pocket, not what the enzyme is for. Reason: SULT1E1 is the physiological human estrogen sulfotransferase, acting at nanomolar estradiol. SULT1A1 sulfates 17beta-estradiol only at high concentrations and shows partial substrate inhibition; in the co-crystal the single bound E2 molecule sits in a non-productive orientation forming a dead-end enzyme-PAP-E2 complex. Retain the annotation as a real but peripheral activity. Supporting Evidence: PMID:16221673 In agreement with previous reports, the enzyme shows partial substrate inhibition at high concentrations of E2. PMID:22069470 displays substrate preference for small phenolic compounds, while SULT1E1 shows a preference for estrogen acceptors |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: A binary SULT1A1-SULT2B1 (UniProtKB:O00204) interaction recovered in a proteome-scale yeast two-hybrid interactome map. The root-level protein binding term identifies no molecular activity for SULT1A1 and does not say what the interaction accomplishes. Reason: Per GO curation guidance, bare protein binding is uninformative and should be replaced by a term describing the actual function. The SULT1A1-SULT2B1 pair is reproducibly detected (UniProt records NbExp=8), but no study has assigned it a function; unlike the SULT4A1 interaction there is no evidence tying it to the conserved dimerization motif, so no heterodimerization term can be justified from this row. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt P50225; O00204: SULT2B1; NbExp=8 |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: The same SULT1A1-SULT2B1 (UniProtKB:O00204) binary interaction, re-detected in a systematic interaction-perturbation screen of disease alleles. Adds no molecular function information for SULT1A1. Reason: Duplicate of the interactome-derived protein binding row; the root-level term is uninformative regardless of how many screens redetect the pair. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: The same SULT1A1-SULT2B1 (UniProtKB:O00204) binary interaction, from a population-scale survey of interaction-disrupting variants. Uninformative for SULT1A1 molecular function. Reason: Duplicate interactome-derived protein binding row with no functional interpretation attached. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: The same SULT1A1-SULT2B1 (UniProtKB:O00204) binary interaction, from cell-line-resolved affinity-purification interactome maps. Uninformative for SULT1A1 molecular function. Reason: Duplicate interactome-derived protein binding row; no mechanism or consequence is reported for the interaction. |
| GO:0004062 aryl sulfotransferase activity | EXP PMID:10199779 Characterization of human iodothyronine sulfotransferases. | ACCEPT | Summary: Recombinant human SULT1A1 sulfates the phenolic 4'-hydroxyl of T4, T3, reverse T3 and 3,3'-T2, with by far the highest affinity of any human SULT tested (Km 0.14 uM for 3,3'-T2 versus 33 uM for SULT1A3). Core catalytic activity. Supporting Evidence: PMID:10199779 The apparent Km values of 3,3'-T2 and T3 ... were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively. |
| GO:0004062 aryl sulfotransferase activity | EXP PMID:16221673 The structure of human SULT1A1 crystallized with estradiol. ... | ACCEPT | Summary: Structural and kinetic characterization of human SULT1A1 co-crystallized with sulfated estradiol and PAP, confirming a functional PAPS-dependent sulfotransferase active site. Supports the core catalytic activity. Supporting Evidence: PMID:16221673 To investigate how estradiol binds to SULT1A1, we co-crystallized SULT1A1 with sulfated estradiol and the cofactor product, PAP (3'-phosphoadenosine 5'-phosphate). |
| GO:0004062 aryl sulfotransferase activity | EXP PMID:21723874 Directed evolution of sulfotransferases and paraoxonases by ... | ACCEPT | Summary: Cytosolic sulfotransferases including SULT1A1 were used as the starting-point enzymes for ancestral-library directed evolution; wild-type and evolved variants were assayed for sulfotransferase activity by HPLC, and an evolved variant was characterized structurally and kinetically. Reason: The cached record is abstract-only, so the per-enzyme assay detail is not visible here; the curator who made this annotation read the full text. The asserted activity is in any case the gene's defining, independently established function, so the annotation is accepted rather than second-guessed. Supporting Evidence: PMID:21723874 Structural and kinetic characterizations of an evolved SULT variant show how few ancestral mutations reshaped the active site and modulated the enzyme's specificity. |
| GO:0004062 aryl sulfotransferase activity | EXP PMID:22069470 The molecular basis for the broad substrate specificity of h... | ACCEPT | Summary: Five crystal structures of human SULT1A1 with PAP and phenolic acceptors (2-naphthol, 3-cyano-7-hydroxycoumarin) plus kinetic characterization of wild-type and engineered variants. The 2-naphthol complex shows the acceptor hydroxyl 2.34 A from the catalytic His108, i.e. a catalytically competent aryl sulfotransferase active site. Supporting Evidence: PMID:22069470 The refined 3D structure of SULT1A1-PAP-2NAP revealed a single 2NAP molecule within pocket-1, positioned in a catalytically competent manner in which the hydroxyl group is positioned 2.34 |
| GO:0004062 aryl sulfotransferase activity | EXP PMID:7834621 Metabolic activation of N-hydroxy arylamines and N-hydroxy h... | ACCEPT | Summary: PAPS-dependent sulfonation of N-hydroxy-arylamines and N-hydroxy heterocyclic amines by human liver cytosol tracked quantitatively with thermostable phenol sulfotransferase (TS-PST, i.e. SULT1A1) activity and was blocked by the SULT1A-selective inhibitor DCNP. Supports the core sulfotransferase activity, here in its procarcinogen-bioactivating mode. Supporting Evidence: PMID:7834621 In the 12 human hepatic cytosols studied, the extent of 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding of the N-hydroxy derivatives were all significantly correlated with levels of thermostable phenol ST (TS-PST) activity but not with thermolabile phenol ST or dehydroepiandrosterone ST activities. |
| GO:0005737 cytoplasm | EXP PMID:8093002 Functional characterization of two human sulphotransferase c... | ACCEPT | Summary: SULT1A1 (HAST1) expressed in COS-7 cells was assayed as a soluble cytosolic enzyme; this is the experimental basis of the UniProt Cytoplasm location. Consistent with the absence of any targeting or membrane-anchoring feature in the sequence. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:8093002} |
| GO:0008146 sulfotransferase activity | IDA PMID:10199779 Characterization of human iodothyronine sulfotransferases. | ACCEPT | Summary: Direct assay of recombinant human SULT1A1 sulfating T4, T3, rT3 and 3,3'-T2. The general term is correct; the same reference already carries the specific child GO:0004062 as an EXP annotation, since the sulfonate is transferred to the phenolic 4'-hydroxyl of the iodothyronine outer ring and UniProt maps these reactions (RHEA:67876, 67888, 67892, 83575) to EC 2.8.2.1. Reason: Kept as the general parent rather than modified: replacing it with GO:0004062 would simply duplicate the GO:0004062 EXP row drawn from this same paper. What is genuinely missing is a term for the reaction actually assayed - GO has no iodothyronine or thyroid-hormone sulfotransferase activity term at all, which is raised in proposed_new_terms. Supporting Evidence: PMID:10199779 In all cases, the substrate preference was 3,3'-T2 >> rT3 > T3 > T4. file:human/SULT1A1/SULT1A1-uniprot.txt Catalyzes the sulfation of T4 (L-thyroxine/3,5,3',5'-tetraiodothyronine), T3 (3,5,3'-triiodothyronine), rT3 (3,3',5'-triiodothyronine) and 3,3'-T2 (3,3'-diiodothyronine), with a substrate preference of 3,3'-T2 > rT3 > T3 > T4. |
| GO:0042403 thyroid hormone metabolic process | IDA PMID:10199779 Characterization of human iodothyronine sulfotransferases. | ACCEPT | Summary: Sulfation of iodothyronines is a principal route of thyroid hormone metabolism, committing the hormone to inactivation and to deiodinase-mediated degradation. SULT1A1 has the highest affinity for both iodothyronines and PAPS of the human SULTs assayed (Km 0.14 uM for 3,3'-T2), making this a core, not peripheral, biological role. Supporting Evidence: PMID:10199779 Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase Knowledge gap: Whether SULT1A1 is the enzyme that actually performs the bulk of thyroid hormone sulfation in vivo is undetermined; its dominance in vitro rests on affinity measurements with recombinant enzyme, not on flux measurements or loss-of-function data in human tissue. BIOLOGY BP_DARK Resolve: Isoform-resolved flux measurement in human hepatocytes with SULT1A1 knockdown or knockout, and quantification of circulating T3S/T4S in individuals stratified by SULT1A1 genotype and copy number. "SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney." — PMID:10199779 |
| GO:0051923 sulfation | IDA PMID:10199779 Characterization of human iodothyronine sulfotransferases. | ACCEPT | Summary: Direct demonstration that recombinant human SULT1A1 catalyses PAPS-dependent sulfation. Correct core biological process. Supporting Evidence: PMID:10199779 We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3 |
| GO:0004062 aryl sulfotransferase activity | IDA PMID:8093002 Functional characterization of two human sulphotransferase c... | ACCEPT | Summary: COS-7-expressed SULT1A1 (HAST1) sulfates the model phenol 4-nitrophenol with Km 0.6 uM, and its DCNP inhibition and thermostability profiles match liver cytosolic P-PST. This is the classic demonstration of the gene's defining phenol-sulfating activity. Supporting Evidence: PMID:8093002 COS-expressed HAST1 was shown to be enzymatically active in sulphating p-nitrophenol with high affinity (Km 0.6 microM), whereas dopamine was the preferred substrate for HAST3 (Km 9.7 microM). |
| GO:0042420 dopamine catabolic process | IDA PMID:8093002 Functional characterization of two human sulphotransferase c... | MARK AS OVER ANNOTATED | Summary: SULT1A1 can sulfate dopamine, but only as a poor secondary substrate: Km 345 uM with Vmax 0.16 nmol/min/mg, against Km 0.6 uM for 4-nitrophenol in the same study. The authors of the cited paper explicitly frame this as a cross-reaction. Reason: The very paper supplying this IDA distinguishes the phenol-sulfating (P-PST, SULT1A1) and monoamine-sulfating (M-PST, SULT1A3) forms and reports that each sulfates the other's substrate with a Km at least two orders of magnitude worse. SULT1A3 (Km 9.7 uM for dopamine) is the physiological catecholamine sulfotransferase; annotating SULT1A1 to dopamine catabolic process implies a dedicated role in monoamine disposal that the kinetics do not support. The row is retained but flagged rather than removed, since the activity itself is real and UniProt records both dopamine 3-O- and 4-O-sulfate reactions. The division of labour is not merely kinetic: it has a known structural basis. Dajani et al. mapped SULT1A3's catecholamine preference to a single acceptor-pocket residue, Glu146, and showed that the E146A substitution alone converts SULT1A3's catalytic properties and substrate preference to resemble SULT1A1's. SULT1A1 carries Ala at that position. So the residue that makes an enzyme a dopamine sulfotransferase is precisely the one SULT1A1 lacks, which is a strong independent argument that dopamine disposal is SULT1A3's role rather than a shared one. Supporting Evidence: PMID:9855620 The change of a single amino acid, E146A, was sufficient to transform the catalytic properties and substrate preference of SULT1A3, such that they closely resembled those of SULT1A1. PMID:9855620 a SULT isoform (SULT1A3 or the monoamine-sulfating form of phenolsulfotransferase) has evolved with considerable selectivity for dopamine and other biogenic amines PMID:8093002 HAST1 could also sulphate dopamine, as could HAST3 sulphate p-nitrophenol, but the Km for these reactions were at least two orders of magnitude greater than for the preferred substrates. PMID:8093002 These appear to encode the two major forms of phenol sulphotransferase (PST) characterized in a number of human tissue cytosols, these being the phenolsulphating (P-PST) and monoamine-sulphating (M-PST) forms of phenol sulphotransferase. |
| GO:0047894 flavonol 3-sulfotransferase activity | IDA PMID:20056724 Phase II metabolism of hesperetin by individual UDP-glucuron... | MODIFY | Summary: The cited study is about hesperetin, and reports that SULT1A1 preferentially and most efficiently forms hesperetin 3'-O-sulfate. GO:0047894 is defined by a different reaction - quercetin to quercetin 3-sulfate - which the reported SULT1A1 product does not match. Reason: Two mismatches with the term definition. (i) Substrate class: hesperetin (4'-methoxy-3',5,7-trihydroxyflavanone) is a flavanone, not a flavonol; it lacks the 3-hydroxyl on the C-ring that defines flavonols and that the flavonol 3-sulfotransferase reaction requires, so no assay on hesperetin can demonstrate flavonol 3-sulfotransferase activity. (ii) Position: the SULT1A1 product named in the abstract is the 3'-O-sulfate on the B-ring, not a 3-sulfate. GO:1990135 flavonoid sulfotransferase activity states the generic flavonoid + PAPS reaction and is the term the evidence supports. Note this is a lateral move, not a generalization: GO:0047894 and GO:1990135 are siblings under GO:0008146, so the erroneous specific claim is not otherwise retained. Caveat: the cached record is abstract-only (the article is not open access and has no PMC record), so whether quercetin appears anywhere in the full methods could not be checked. The argument above does not depend on that - it rests on hesperetin's structure and on the product the abstract itself names - but a curator with the full text should confirm before the term is changed. Proposed replacements: flavonoid sulfotransferase activity Supporting Evidence: PMID:20056724 SULT1A2 and SULT1A1 catalyze preferably and most efficiently the formation of hesperetin 3'-O-sulfate, and SULT1C4 catalyzes preferably and most efficiently the formation of hesperetin 7-O-sulfate. PMID:20056724 Results demonstrate that hesperetin is conjugated at positions 7 and 3' |
| GO:0005515 protein binding | IPI PMID:32152050 Interaction of the Brain-Selective Sulfotransferase SULT4A1 ... | MODIFY | Summary: Co-immunoprecipitation shows SULT1A1 binding the catalytically inactive brain-selective SULT4A1 (UniProtKB:Q9BR01), and the interaction is abolished by mutating the conserved C-terminal dimerization motif of the sulfotransferases. Unlike the interactome-derived rows, this experiment identifies the interaction surface and so does support a specific molecular function. Reason: The dimerization-motif dependence establishes that SULT1A1 forms a heterodimer with a different sulfotransferase, which is a real, mechanistically meaningful molecular function; the root-level protein binding term discards exactly that information. GO:0046982 protein heterodimerization activity is the informative replacement. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:32152050 Using immunoprecipitation, SULT4A1 was shown to interact with both SULT1A1 and SULT1A3 when expressed in human cells. PMID:32152050 Mutation of the conserved dimerization motif located in the C terminus of the sulfotransferases prevented this interaction. |
| GO:0050427 3'-phosphoadenosine 5'-phosphosulfate metabolic process | IDA PMID:12471039 Structure of a human carcinogen-converting enzyme, SULT1A1. ... | ACCEPT | Summary: SULT1A1 consumes PAPS and releases PAP in every reaction it catalyses; the crystal structure and steady-state kinetics in this paper directly demonstrate the enzyme operating on the PAPS/PAP couple. Correct. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt Reaction=a phenol + 3'-phosphoadenylyl sulfate = an aryl sulfate + adenosine 3',5'-bisphosphate + H(+) |
| GO:0050656 3'-phosphoadenosine 5'-phosphosulfate binding | IDA PMID:12471039 Structure of a human carcinogen-converting enzyme, SULT1A1. ... | ACCEPT | Summary: The crystal structure resolves the bound nucleotide in the conserved PAPS-binding cradle; UniProt records six PAPS-binding regions derived from this and subsequent structures (residues 48-53, 130, 138, 193, 227-232, 255-259). Cofactor binding is an integral part of the catalytic mechanism. Supporting Evidence: PMID:22069470 In all determined structures, as well as in previously described SULT1A1 structures, the PAP moiety is located at the same position in a catalytically competent manner with all binding site residues oriented to minimize conformational freedom of the PAP molecule file:human/SULT1A1/SULT1A1-uniprot.txt BINDING 48..53 |
| GO:0006068 ethanol catabolic process | IDA PMID:23207770 Ethanol sulfation by the human cytosolic sulfotransferases: ... | MARK AS OVER ANNOTATED | Summary: SULT1A1 is one of four human SULTs able to sulfate ethanol to ethyl sulfate. The authors themselves describe ethyl sulfate as a minor direct ethanol metabolite whose interest is as a consumption biomarker, and the highest ethanol-sulfating activity in human tissue was found in small intestine, not in the SULT1A1-dominated liver. Reason: Ethanol is overwhelmingly disposed of by alcohol dehydrogenase and CYP2E1; sulfation accounts for a negligible fraction of ethanol clearance. Annotating SULT1A1 to ethanol catabolic process overstates a quantitatively trivial, non-selective side reaction shared with SULT1A2, SULT1A3 and SULT1C4. Retained rather than removed because the activity is genuine and the ethyl sulfate biomarker is real. Supporting Evidence: PMID:23207770 Ethyl sulfate, a minor and direct ethanol metabolite in adult human body, has been implicated as a biomarker for alcohol consumption and in utero exposure to ethanol. PMID:23207770 A systematic analysis revealed four ethanol-sulfating SULTs, SULT1A1, SULT1A2, SULT1A3, and SULT1C4, among the eleven human SULT enzymes previously prepared and purified. |
| GO:0004062 aryl sulfotransferase activity | IDA PMID:23207770 Ethanol sulfation by the human cytosolic sulfotransferases: ... | MODIFY | Summary: The acceptor assayed in this paper is ethanol, an aliphatic primary alcohol with no aromatic ring. GO:0004062 is defined as PAPS + a phenol = an aryl sulfate + PAP, so this particular experiment does not demonstrate aryl sulfotransferase activity, even though SULT1A1 undoubtedly has that activity on other evidence. Reason: Mis-typed term for the assayed reaction. Ethanol sulfation yields ethyl sulfate, an alkyl sulfate, which is precisely the reaction defining GO:0004027 alcohol sulfotransferase activity (PAPS + an alcohol = PAP + an alkyl sulfate). Replacing the term keeps this genuine finding in the record and makes the annotation set state something the other rows do not - that the acceptor pocket tolerates a non-aromatic alcohol. This is deliberately inconsistent with the nine ACCEPT decisions on GO:0004062 elsewhere in this file: those rest on phenolic acceptors (4-nitrophenol, 2-naphthol, iodothyronines, N-hydroxy-arylamines) and are unaffected, so GO:0004062 remains a correct and well-supported annotation for the gene. Only this row's evidence fails to support it. Proposed replacements: alcohol sulfotransferase activity Supporting Evidence: PMID:23207770 A systematic analysis revealed four ethanol-sulfating SULTs, SULT1A1, SULT1A2, SULT1A3, and SULT1C4, among the eleven human SULT enzymes previously prepared and purified. |
| GO:0050427 3'-phosphoadenosine 5'-phosphosulfate metabolic process | IDA PMID:23207770 Ethanol sulfation by the human cytosolic sulfotransferases: ... | ACCEPT | Summary: Purified SULT1A1 was shown to consume PAPS in transferring sulfonate to ethanol, and the metabolic-labelling experiment followed radiolabelled sulfate through PAPS into ethyl sulfate in HepG2 cells. Correct. Supporting Evidence: PMID:23207770 A systematic analysis revealed four ethanol-sulfating SULTs, SULT1A1, SULT1A2, SULT1A3, and SULT1C4, among the eleven human SULT enzymes previously prepared and purified. |
| GO:0051923 sulfation | IDA PMID:23207770 Ethanol sulfation by the human cytosolic sulfotransferases: ... | ACCEPT | Summary: Direct demonstration of SULT1A1-catalysed sulfation, here of ethanol. Correct core biological process, independent of the concerns about the specific ethanol catabolic process and aryl sulfotransferase rows from the same paper. Supporting Evidence: PMID:23207770 Of the three human organs, the small intestine displayed the highest activity. |
| GO:0008146 sulfotransferase activity | IDA PMID:19548878 Inhibitory effects of kynurenic acid, a tryptophan metabolit... | ACCEPT | Summary: Recombinant human SULT1A1 activity was measured directly in order to characterize its inhibition by kynurenic acid; kynurenic acid itself was shown not to be a substrate, so the assay is a bona fide measurement of SULT1A1 sulfotransferase activity toward its own acceptors. Reason: The paper's purpose is inhibitor characterization rather than substrate discovery, so the general term is appropriate here: the abstract does not identify which acceptor was used for the hSULT1A1 assays, and inventing a more specific term would go beyond the evidence. Supporting Evidence: PMID:19548878 KYNA also exerted an inhibitory activity towards hSULT1A1 and hSULT1B1. PMID:19548878 No sulfate metabolite of KYNA was detected with mouse and human SULTs examined under the conditions used, suggesting that it is a bona fide inhibitor of SULTs. |
| GO:0051923 sulfation | IDA PMID:19548878 Inhibitory effects of kynurenic acid, a tryptophan metabolit... | ACCEPT | Summary: Correct biological process, but carrying an inappropriate qualifier. SULT1A1 is the enzyme that performs the sulfonate transfer, so it is involved_in sulfation, not merely acts_upstream_of_or_within it; acts_upstream_of_or_within is intended for gene products whose relationship to a process is indirect or unresolved. Reason: The term itself is right and is the gene's core process, so the row is kept. The recommended curation fix is a qualifier change to involved_in, which would make it consistent with the four other sulfation rows on this gene (IBA and three IDA) that already use involved_in. The review schema records term-level, not qualifier-level, replacements, so the correction is noted here. Supporting Evidence: PMID:19548878 KYNA also exerted an inhibitory activity towards hSULT1A1 and hSULT1B1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-158468 | ACCEPT | Summary: Reactome places the SULT1A1-catalysed sulfonation of paracetamol (acetaminophen) in the cytosol, acting as a homodimer. Correct and more precise than the cytoplasm rows. Supporting Evidence: Reactome:R-HSA-158468 Cytosolic sulfotransferase 1A1 (SULT1A1), in dimeric form, can sulfonate the widely used analgesic and antipyretic drug paracetamol (PARA aka acetaminophen). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-158849 | ACCEPT | Summary: Reactome's generic phenol sulfate-conjugation reaction, explicitly assigned to the cytosol and to the aryl sulfotransferase activity of the SULT1A1 homodimer. Correct. Supporting Evidence: Reactome:R-HSA-158849 This reaction takes place in the 'cytosol' and is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer'. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-158860 | ACCEPT | Summary: Reactome's SULT1A1-catalysed sulfonation of the genotoxic metabolite N-hydroxy-4-aminobiphenyl, placed in the hepatic cytosol. Correct; redundant with the other six cytosol rows. Supporting Evidence: Reactome:R-HSA-158860 It can be sulfonated in the liver by cytosolic sulfotransferase 1A1 (SULT1A1) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-176474 | ACCEPT | Summary: Reactome's 3,3'-diiodothyronine sulfation reaction, placed in the cytosol. Correct; redundant with the other cytosol rows. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-176585 | ACCEPT | Summary: Reactome's 3,5,3'-triiodothyronine (T3) sulfation reaction, placed in the cytosol. Correct; redundant with the other cytosol rows. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-176646 | ACCEPT | Summary: Reactome's 4-nitrophenol sulfation reaction, placed in the cytosol. Correct; redundant with the other cytosol rows. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9753277 | ACCEPT | Summary: Reactome's acetaminophen sulfation reaction, catalysed by SULT dimers including SULT1A1 and placed in the cytosol. Correct; redundant with the other cytosol rows. Supporting Evidence: Reactome:R-HSA-9753277 SULTs 1A1, 1A3, 1A4, 1C4, 1E1 and 2A1 are known to have sulfotransferase activity towards APAP |
| GO:0004062 aryl sulfotransferase activity | IDA PMID:12471039 Structure of a human carcinogen-converting enzyme, SULT1A1. ... | ACCEPT | Summary: Crystal structure of human SULT1A1 with the phenolic xenobiotic p-nitrophenol bound in the acceptor site, together with steady-state kinetics showing substrate inhibition. Direct structural and kinetic support for the core aryl sulfotransferase activity. Supporting Evidence: PMID:12471039 The crystal structure of human SULT1A1 reported here is the first sulfotransferase structure complexed with a xenobiotic substrate. |
| GO:0006805 xenobiotic metabolic process | IDA PMID:12471039 Structure of a human carcinogen-converting enzyme, SULT1A1. ... | ACCEPT | Summary: Phase II conjugation of drugs and environmental chemicals is the central biological role of SULT1A1: it is the dominant hepatic sulfotransferase and handles acetaminophen, minoxidil, simple phenols and procarcinogenic N-hydroxy-arylamines. Core biological process. Supporting Evidence: PMID:12471039 A major human sulfotransferase, SULT1A1, metabolizes and/or bioactivates many endogenous compounds and is implicated in a range of cancers because of its ability to modify diverse promutagen and procarcinogen xenobiotics. PMID:12471039 Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. |
| GO:0008210 estrogen metabolic process | IDA PMID:16221673 The structure of human SULT1A1 crystallized with estradiol. ... | KEEP AS NON CORE | Summary: SULT1A1 does sulfate 17beta-estradiol to estradiol 3-sulfate (RHEA:52372), and the co-crystal structure shows how the acceptor pocket rearranges to admit a fused-ring steroid. But this is a low-affinity, substrate-inhibited reaction of an enzyme built for small phenols, whereas SULT1E1 is the dedicated, nanomolar-affinity human estrogen sulfotransferase. Reason: A genuine but peripheral activity. In the structure reported here the single estradiol molecule is bound in a non-productive orientation, forming the dead-end enzyme-PAP-E2 complex that explains the substrate inhibition - direct evidence that estradiol is a poor fit for this active site. Estrogen homeostasis should not be presented as part of SULT1A1's core function. Supporting Evidence: PMID:16221673 The crystal structure of SULT1A1 that we present here has PAP and one molecule of E2 bound in a nonproductive mode in the active site. PMID:22069470 displays substrate preference for small phenolic compounds, while SULT1E1 shows a preference for estrogen acceptors |
| GO:0050294 steroid sulfotransferase activity | IDA PMID:16221673 The structure of human SULT1A1 crystallized with estradiol. ... | KEEP AS NON CORE | Summary: Direct evidence that SULT1A1 sulfates the phenolic A-ring hydroxyl of 17beta-estradiol, matching the term definition (PAPS + a phenolic steroid = PAP + steroid O-sulfate). Real activity, but a low-affinity, substrate-inhibited one that does not represent what the enzyme is for. Reason: Same rationale as the estrogen metabolic process row: retained as a genuine demonstrated activity, but not core. SULT1E1 and SULT2A1/SULT2B1 are the dedicated human steroid sulfotransferases. Supporting Evidence: PMID:16221673 Human SULT1A1 belongs to the supergene family of sulfotransferases (SULTs) involved in the sulfonation of xeno- and endobiotics. file:human/SULT1A1/SULT1A1-uniprot.txt Reaction=17beta-estradiol + 3'-phosphoadenylyl sulfate = 17beta-estradiol 3-sulfate + adenosine 3',5'-bisphosphate + H(+) |
| GO:0006805 xenobiotic metabolic process | IDA PMID:20056724 Phase II metabolism of hesperetin by individual UDP-glucuron... | ACCEPT | Summary: Sulfation of the dietary flavanone hesperetin by SULT1A1 is part of the phase II first-pass metabolism of a non-nutrient dietary xenobiotic in gut and liver. Correct and core. Supporting Evidence: PMID:20056724 Phase II metabolism by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the predominant metabolic pathway during the first-pass metabolism of hesperetin |
| GO:0009812 flavonoid metabolic process | IDA PMID:20056724 Phase II metabolism of hesperetin by individual UDP-glucuron... | ACCEPT | Summary: SULT1A1 is one of the two most efficient human SULTs for hesperetin conjugation, forming the 3'-O-sulfate. Conjugation of dietary polyphenols is a substantial part of what SULT1A1 does in gut and liver, so this process term is well placed. Supporting Evidence: PMID:20056724 SULT1A2 and SULT1A1 catalyze preferably and most efficiently the formation of hesperetin 3'-O-sulfate, and SULT1C4 catalyzes preferably and most efficiently the formation of hesperetin 7-O-sulfate. |
| GO:0051923 sulfation | IDA PMID:20056724 Phase II metabolism of hesperetin by individual UDP-glucuron... | ACCEPT | Summary: Direct demonstration of SULT1A1-catalysed sulfation, here of hesperetin. Correct core biological process. Supporting Evidence: PMID:20056724 Results demonstrate that hesperetin is conjugated at positions 7 and 3' |
| GO:0008146 sulfotransferase activity | TAS PMID:8661000 Human phenol sulfotransferase STP2 gene: molecular cloning, ... | ACCEPT | Summary: A legacy traceable-author-statement annotation. The term is unquestionably correct for SULT1A1 and is supported many times over by direct experimental evidence, so the row stands on its merits - but the reference it cites is a genomic-structure paper about the paralogous STP2 gene, which is SULT1A2 (P50226), not SULT1A1 (whose historical aliases are STP and STP1). Reason: Kept because sulfotransferase activity is the gene's defining function and is independently established by two IDA rows, five EXP rows, an IBA and four crystal structures. It is not, however, established by this reference: the project curator has read the full text and confirms the paper contains no enzymology of its own - the sulfotransferase statements in it are background about the thermostable PST form in general, and SULT1A1/STP1 appears only as a sequence comparison (96% identical protein). The recommended curation action is therefore to re-source the annotation to a paper that actually assays SULT1A1, or to retire it as redundant with the experimental rows, rather than to rely on this citation. See reference_review on PMID:8661000. Supporting Evidence: PMID:8661000 The thermostable (TS) form of phenol sulfotransferase (PST) preferentially catalyzes the sulfonation of "simple" planar phenols PMID:8661000 Two different human liver TS PST cDNAs have been cloned that encode proteins with amino acid sequences that are 96% identical. |
| GO:0009308 amine metabolic process | TAS PMID:8661000 Human phenol sulfotransferase STP2 gene: molecular cloning, ... | MARK AS OVER ANNOTATED | Summary: A very general biological process asserted from a reference that characterizes a different gene and contains no enzymology at all. The cited paper determines the exon structure, alternative 5' ends and chromosomal location of the STP2 gene (SULT1A2); the only statement in it that concerns amines is a generic family-level background clause, which is almost certainly where the term came from. Reason: Three problems compound here. (i) Provenance: PMID:8661000 is a gene-structure study of STP2, which UniProt assigns to SULT1A2 (P50226, gene-name line "Name=SULT1A2; Synonyms=STP2"), whereas SULT1A1's synonyms are STP and STP1; it is reference 4 of the P50226 entry. SULT1A1/STP1 appears in the paper only as a sequence comparison - the protein it encodes is noted as 96% identical to STP2's - alongside STM/SULT1A3, STE/SULT1E1 and rat and guinea-pig genes used for splice-junction comparison; none of these is characterized here. (ii) No supporting experiment: the project curator has read the full text and confirms the paper reports no new enzymology of any kind - no recombinant enzyme assays, no substrate-specificity experiments, no Km/Vmax or catalytic-rate measurements, no thermostability assays, and no functional comparison of the STP1 and STP2 proteins. The new results are entirely molecular genetics (genomic cloning and sequencing, a nine-exon structure, two alternative noncoding first exons IA and IB that are alternative 5' UTRs rather than additional genes, promoter analysis, and chromosome-16 localization), explicitly framed as enabling later study of how enzyme activity is regulated. (iii) Poor fit: SULT1A1 is the phenol-preferring form, and monoamine sulfation is the province of SULT1A3; SULT1A1's amine-containing substrates (dopamine, N-hydroxy-arylamines) are sulfonated on oxygen, not on nitrogen, so even the chemistry the term suggests is not what this enzyme does. The likely origin of the annotation is the opening background sentence quoted below, which lists neurotransmitters among the things sulfonation acts on - a statement about the SULT family in general, not about this gene or this paper's results. On this evidence REMOVE would also be defensible, since a TAS with no traceable statement supporting it for this gene is not a valid TAS; MARK_AS_OVER_ANNOTATED is used because the term is not biologically false of SULT1A1, which does act on amine-bearing molecules. Either way it should be retired or replaced with a substrate-specific term. Supporting Evidence: PMID:8661000 We have determined the structure and chromosomal localization of the gene for one of these two cDNAs, STP2, as a step toward understanding molecular genetic mechanisms involved in the regulation of this enzyme activity in humans. PMID:8661000 Sulfonation is an important pathway in the biotransformation of many drugs, xenobiotics, neurotransmitters, and steroid hormones. |
| GO:0042803 protein homodimerization activity | IDA PMID:12471039 Structure of a human carcinogen-converting enzyme, SULT1A1. ... | NEW | Summary: SULT1A1 is an obligate homodimer. UniProt records SUBUNIT "Homodimer" with three independent ECO:0000269 experimental references (PubMed:12471039, PubMed:16221673, PubMed:20417180), the crystal structures are solved as dimers, and Reactome models every SULT1A1 reaction as being catalysed by the "SULT1A1 dimer" / "SULT1A1 homodimer". Dimerization is mediated by the conserved C-terminal KTVE motif shared across the cytosolic SULTs, the same motif whose mutation abolishes the SULT1A1-SULT4A1 interaction. Reason: Current GOA contains no dimerization term for SULT1A1, only four bare protein binding rows from interactome screens. The homodimer is the catalytically relevant species in both the structural literature and the Reactome pathway model, so its absence is a real annotation gap rather than a stylistic one. Supporting Evidence: file:human/SULT1A1/SULT1A1-uniprot.txt SUBUNIT: Homodimer. PMID:20417180 The conformational differences between the two structures revealed a plastic substrate-binding pocket with two channels and a switch-like substrate selectivity residue Phe247, providing clearly a structural basis for the substrate inhibition. Reactome:R-HSA-158849 is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer' PMID:32152050 Mutation of the conserved dimerization motif located in the C terminus of the sulfotransferases prevented this interaction. |
Loading supporting content…
Download this section (compressed HTML)Q: Is SULT1A1 the enzyme that performs the bulk of iodothyronine sulfation in human liver and kidney, or does its sub-micromolar Km simply make it the best-performing isoform in vitro? The question posed in 1999 does not appear to have been settled.
Suggested experts: Theo J. Visser, Michael W. H. Coughtrie
Q: Should the seven duplicate Reactome-derived cytosol rows, and the parallel cytoplasm rows from IBA, IEA and EXP, be consolidated? Nine cellular-component annotations currently assert one uncontroversial fact.
Q: Does the SULT1A1-SULT2B1 interaction detected in four independent large-scale screens (UniProt NbExp=8) reflect heterodimerization through the conserved KTVE motif, as demonstrated for SULT4A1, or is it an artefact of the assay formats?
Suggested experts: Rodney F. Minchin, Neville J. Butcher
Experiment: Generate SULT1A1 knockout and SULT1A3/SULT1B1/SULT1E1 single- and multi-knockout human hepatocyte lines (or primary hepatocytes with isoform-selective siRNA), then measure T4, T3, rT3 and 3,3'-T2 sulfate output by LC-MS/MS at physiological substrate concentrations. Pair with genotype- and copy-number-stratified measurement of circulating T3 sulfate in a human cohort.
Hypothesis: SULT1A1 is the dominant iodothyronine sulfotransferase in human liver, and common SULT1A1 genotypes and copy numbers therefore modulate thyroid hormone disposal.
Type: isoform-selective knockout plus targeted LC-MS/MS metabolite flux
Experiment: Compare 4-EPS production from orally administered 4-ethylphenol in Sult1a1-null, wild-type and SULT1A1-humanized mice, with tissue-resolved sampling of gut, portal blood, liver and brain. In parallel, measure 4-EP sulfation kinetics for each recombinant human SULT isoform to establish whether SULT1A1's Km is competitive at physiological 4-EP concentrations.
Hypothesis: Sulfation of 4-ethylphenol to the neuroactive metabolite 4-EPS is carried out by SULT1A1 in the intestinal epithelium.
Type: knockout and humanized mouse pharmacokinetics with recombinant-enzyme kinetics
Experiment: Repeat co-immunoprecipitation of SULT1A1 with SULT2B1 in human cells using wild-type SULT1A1 and a KTVE-motif mutant, alongside size-exclusion chromatography with multi-angle light scattering to establish the oligomeric state of the co-expressed pair. The same design already resolved the SULT1A1-SULT4A1 case.
Hypothesis: The bare protein binding annotations to SULT2B1 reflect KTVE-motif-dependent heterodimerization, in which case they should carry GO:0046982 rather than GO:0005515.
Type: co-immunoprecipitation with dimerization-motif mutants plus SEC-MALS
Experiment: Perform untargeted sulfo-metabolomics (negative-mode LC-MS with neutral-loss scanning for the sulfonate group) on SULT1A1-null versus isogenic wild-type human hepatocyte and intestinal enteroid models under unchallenged conditions, and validate any differential sulfoconjugate against recombinant enzyme.
Hypothesis: SULT1A1 has an endogenous acceptor that has not yet been identified, beyond the iodothyronines.
Type: untargeted sulfo-metabolomics in isogenic knockout models
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The site at which the gut-microbial metabolite 4-ethylphenol is sulfated to 4-EPS in vivo, and whether SULT1A1 is the enzyme that does it, are unknown - the attribution rests on in vitro biochemistry with recombinant enzyme.
BIOLOGYCURATION BP_DARK
What is known: Established: 4-ethylphenol is sulfated to 4-EPS by SULT1A1 and other sulfotransferases in vitro (UniProt RHEA:70607, ECO:0000269|PubMed:35165440); 4-EPS enters the brain, impairs oligodendrocyte maturation and myelination, and produces anxiety-like behaviour in mice.
Significance: If SULT1A1 is the principal 4-EP sulfotransferase, a common polymorphic xenobiotic-metabolizing enzyme would sit directly on a gut-microbiome-to-brain axis, and this activity is currently absent from GOA altogether.
What would resolve it: Tissue-resolved measurement of 4-EP sulfation in Sult1a1-null versus humanized-SULT1A1 mice, and isoform-selective inhibition or knockdown in human intestinal and hepatic models. Curation-side, an annotation for 4-ethylphenol sulfation should be added from PMID:35165440 / RHEA:70607.
Provenance (the field's own admissions):
Gap: No endogenous metabolite has been shown to depend on SULT1A1 in vivo, and a comparative-evolution test now argues that the original framing of this gap was wrong: the acceptor pocket shows no sign of being tuned to a dedicated endogenous acceptor, so what remains open is which substrates matter physiologically for a broad-specificity enzyme, not which single acceptor it evolved for.
NARROWING BIOLOGY MF_DARK
What is known: Established: the active site is small, hydrophobic and conformationally plastic, which is the structural explanation for the broad specificity; the enzyme sulfates iodothyronines with sub-micromolar affinity and estradiol, dopamine and ethanol with far weaker affinity. Newly established by comparative analysis: the pocket is less conserved than the protein scaffold across SULT1A1 orthologs (0.836 vs 0.868 mean identity) and is the most divergent region across the human SULT1 paralogs (0.511 vs 0.629), the signature of a specificity-diversifying module rather than a lock-and-key site. Two pocket residues are poorly conserved even among mammalian orthologs (Phe247 identity 0.20, Ile89 0.50), Phe247 carries a common human missense variant, and gnomAD shows no pocket-specific depletion of missense variation. The classic low-activity allele Arg213His lies outside the pocket entirely. Caveat: the individual pocket-versus-scaffold statistical tests are non-significant (n = 11 pocket residues), so this is an absence of evidence for focused constraint, with three independent lines trending the same way, rather than positive proof of promiscuity.
Significance: Distinguishing a dedicated endogenous substrate from generalized chemical defence determines whether SULT1A1's core function should be modelled as a metabolic step in a named pathway or as a detoxification activity with no fixed input. The comparative evidence now favours the latter, which supports retaining the broad aryl/phenol sulfotransferase molecular function and argues against narrowing SULT1A1 to a dedicated acceptor. Note that within the SULT1A subfamily dedicated specificity does exist, but in the paralog: SULT1A3's preference for catecholamines is conferred by the single pocket-region residue Glu146, where SULT1A1 has Ala.
What would resolve it: The evolutionary half is addressed. What remains is the physiological half: untargeted sulfo-metabolomics comparing SULT1A1-null and wild-type human hepatocyte and enteroid models, to identify which endogenous sulfoconjugates actually depend on the enzyme in the absence of a dedicated acceptor.
Provenance (the field's own admissions):
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)