DHDDS is the catalytic subunit of the human cis-prenyltransferase (cis-PT / dehydrodolichyl diphosphate synthase) complex. Together with the non-catalytic subunit NUS1 (Nogo-B receptor, NgBR), it catalyzes the committed step of dolichol biosynthesis: the Mg2+-dependent, sequential cis (Z)-condensation of many isopentenyl diphosphate (IPP) units onto the allylic primer (2E,6E)-farnesyl diphosphate (FPP) to form long-chain ditrans,polycis-polyprenyl (dehydrodolichyl) diphosphate (predominantly C95-C100). This product is the precursor of dolichyl phosphate (Dol-P), the obligate glycan carrier lipid used in N-linked protein glycosylation, O-mannosylation, and GPI-anchor biosynthesis. The active enzyme is a heterotetramer (a dimer of DHDDS-NUS1 heterodimers); the single active site lies entirely within DHDDS, while NUS1 is a pseudo-cis-prenyltransferase that contributes a C-terminal RXG motif to the DHDDS active site and allosterically enhances activity. DHDDS is a peripheral membrane protein of the endoplasmic reticulum. In humans, DHDDS variants cause autosomal recessive retinitis pigmentosa 59 and a dominant developmental and epileptic encephalopathy, and severe loss of activity can present as a congenital disorder of glycosylation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016094 polyprenol biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: DHDDS/cis-PT synthesizes the long-chain polyprenyl (dehydrodolichyl) diphosphate that is the polyprenol/dolichol precursor, so this phylogenetically inferred pathway process is correct for the gene. It is a broader framing of the same dolichol-precursor biosynthesis captured more specifically by GO:0006489 and GO:0043048; retained as a valid biological-process annotation. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt Synthesizes long-chain polyprenols |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Correct localization but non-specific: DHDDS acts at the ER membrane, which is captured more precisely by GO:0005789 (endoplasmic reticulum membrane, IDA in PMID:14652022). Kept as a broader, correct compartment annotation. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt Endoplasmic reticulum membrane |
| GO:0045547 ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core molecular function. This is the specific cis-prenyltransferase activity of the DHDDS/NUS1 complex (EC 2.5.1.87, RHEA:53008). Directly supported by experimental annotations (EXP/IDA) from multiple structural and biochemical studies; the phylogenetic inference agrees with the experimental evidence. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt EC=2.5.1.87 |
| GO:1904423 dehydrodolichyl diphosphate synthase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Correct. DHDDS is a subunit of the dehydrodolichyl diphosphate synthase (cis-PT) complex with NUS1. The phylogenetic inference matches direct experimental evidence (IDA/IPI in PMID:28842490 and PMID:32817466). Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt With NUS1, forms the dehydrodolichyl diphosphate synthase |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct location, matching the experimentally determined ER membrane localization. This IEA (from UniProt subcellular-location mapping) is redundant with the IDA in PMID:14652022 but records the gene's own correct compartment, so it is accepted rather than flagged as over-annotation. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt Endoplasmic reticulum membrane |
| GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct branch but a high-level parent of the specific activity. DHDDS's true function is the specific cis-prenyltransferase GO:0045547 (which is a descendant of this term). This InterPro-derived general term is an over-annotation relative to the well-supported specific catalytic term. Proposed replacements: ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt EC=2.5.1.87 |
| GO:0045547 ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity | IEA GO_REF:0000120 | ACCEPT | Summary: Correct core molecular function, derived automatically from the EC 2.5.1.87 / RHEA:53008 mapping. This matches the experimentally established activity; accepted as the gene's own core catalytic function (not flagged as redundant over-annotation). Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt EC=2.5.1.87 |
| GO:0005515 protein binding | IPI PMID:32817466 Structural elucidation of the cis-prenyltransferase NgBR/DHD... | MARK AS OVER ANNOTATED | Summary: This IPI records the physical interaction with NUS1 (UniProtKB:Q96E22), the partner subunit of the cis-PT complex. The interaction is real and central, but bare "protein binding" is uninformative; the meaningful capture is complex membership (GO:1904423). Marked as over-annotated rather than removed (experimental IPI). Proposed replacements: dehydrodolichyl diphosphate synthase complex Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt The active dehydrodolichyl diphosphate synthase complex is a |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput affinity-purification/BioPlex interactome IPI, again capturing the DHDDS-NUS1 (Q96E22) interaction. Real but uninformative as bare "protein binding"; the biologically meaningful term is complex membership (GO:1904423). Over-annotation, not removed (experimental IPI). Proposed replacements: dehydrodolichyl diphosphate synthase complex Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt The active dehydrodolichyl diphosphate synthase complex is a |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:32817466 Structural elucidation of the cis-prenyltransferase NgBR/DHD... | ACCEPT | Summary: Author-stated ER membrane localization (ComplexPortal), consistent with the experimentally determined location. Correct compartment for the gene; accepted. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006489 dolichyl diphosphate biosynthetic process | IDA PMID:32817466 Structural elucidation of the cis-prenyltransferase NgBR/DHD... | ACCEPT | Summary: Core biological process: the direct product of DHDDS/cis-PT is dehydrodolichyl (polyprenyl) diphosphate, the dolichyl-diphosphate precursor. Well supported by the structural/biochemical characterization of the human cis-PT complex. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt a precursor of dolichol |
| GO:1904423 dehydrodolichyl diphosphate synthase complex | IPI PMID:32817466 Structural elucidation of the cis-prenyltransferase NgBR/DHD... | ACCEPT | Summary: Correct core complex annotation. The crystal structure of the human NgBR/DHDDS (NUS1/DHDDS) complex directly demonstrates that DHDDS is a subunit of the cis-PT (dehydrodolichyl diphosphate synthase) complex. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt The active dehydrodolichyl diphosphate synthase complex is a |
| GO:0043048 dolichyl monophosphate biosynthetic process | IDA PMID:28842490 A conserved C-terminal RXG motif in the NgBR subunit of cis-... | ACCEPT | Summary: Core biological process. DHDDS catalyzes the first committed step of the dolichyl phosphate (Dol-P) biosynthetic pathway; PMID:28842490 characterizes the purified heteromeric cis-PT and shows both subunits function in catalysis and substrate binding, tying the enzyme to Dol-P/polyprenol synthesis. Supporting Evidence: PMID:28842490 cis-PT is the first enzyme committed to the synthesis of dolichyl phosphate |
| GO:0043048 dolichyl monophosphate biosynthetic process | IDA PMID:33077723 Structural basis of heterotetrameric assembly and disease mu... | ACCEPT | Summary: Core biological process, supported by structural and enzymatic characterization of the human cis-PT complex, whose dehydrodolichyl diphosphate product feeds dolichol-phosphate synthesis. Supporting Evidence: PMID:33077723 DHDD is the precursor for dolichol-phosphate |
| GO:0004659 prenyltransferase activity | IDA PMID:25066056 Mutation of Nogo-B receptor, a subunit of cis-prenyltransfer... | MODIFY | Summary: Correct but too general. PMID:25066056 experimentally reconstitutes cis-PTase activity from human hCIT (DHDDS) plus NgBR. The activity is more precisely the specific cis-prenyltransferase GO:0045547 (a descendant of prenyltransferase activity), which is separately and well supported. Modify to the specific term. Proposed replacements: ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity Supporting Evidence: PMID:25066056 only co-translation of Nus1 with Rer2 and its orthologs in S.pombe or humans, formed an active cis-PTase complex |
| GO:0045547 ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity | EXP PMID:25066056 Mutation of Nogo-B receptor, a subunit of cis-prenyltransfer... | ACCEPT | Summary: Core molecular function with direct experimental support. Human hCIT (DHDDS) co-expressed with NgBR forms an active cis-PTase that condenses IPP with FPP to make polyprenyl pyrophosphate. This is the gene's defining catalytic activity. Supporting Evidence: PMID:25066056 only co-translation of Nus1 with Rer2 and its orthologs in S.pombe or humans, formed an active cis-PTase complex |
| GO:0045547 ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity | EXP PMID:32817466 Structural elucidation of the cis-prenyltransferase NgBR/DHD... | ACCEPT | Summary: Core molecular function, experimentally supported. The human NgBR/DHDDS cis-PTase catalyzes the rate-limiting synthesis of the long-chain glycosyl carrier lipid precursor; the crystal structure resolves the DHDDS active site with bound FPP. Supporting Evidence: PMID:32817466 Cis-prenyltransferase (cis-PTase) catalyzes the rate-limiting step in the synthesis of glycosyl carrier lipids required for protein glycosylation |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:14652022 Identification and characterization of a cDNA encoding a lon... | ACCEPT | Summary: Core localization with direct experimental support. The human cis-isoprenyltransferase (hCIT/DHDDS) is an ER enzyme; overexpressed hCIT gives a 38 kDa polypeptide that colocalizes with calnexin in the ER, the site of Dol-P biosynthesis. Supporting Evidence: PMID:14652022 co-localizes with calnexin in the ER, the site of Dol-P biosynthesis |
| GO:0045547 ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity | IDA PMID:33077723 Structural basis of heterotetrameric assembly and disease mu... | ACCEPT | Summary: Core molecular function, directly supported by the crystal structure and in vitro activity of the human cis-PT complex. The single catalytic active site is entirely within DHDDS, which binds FPP (S1), IPP (S2) and Mg2+; NUS1 is catalytically quiescent. `enables` is appropriate given the active site resides in DHDDS. Supporting Evidence: PMID:33077723 the only active-site of the complex is situated within the cis-prenyltransferase homology domain of DHDDS |
| GO:0045547 ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity | IDA PMID:28842490 A conserved C-terminal RXG motif in the NgBR subunit of cis-... | ACCEPT | Summary: Core molecular function. PMID:28842490 established the first purification of the heteromeric cis-PT and showed both NgBR and hCIT (DHDDS) subunits function in catalysis and substrate binding. The `contributes_to` qualifier reflects the complex context; the activity itself is correct and central. Supporting Evidence: PMID:28842490 both NgBR and hCIT subunits function in catalysis and substrate binding |
| GO:1904423 dehydrodolichyl diphosphate synthase complex | IDA PMID:28842490 A conserved C-terminal RXG motif in the NgBR subunit of cis-... | ACCEPT | Summary: Correct core complex annotation, directly supported by the purification and characterization of the heteromeric NgBR/hCIT (NUS1/DHDDS) cis-PT complex. Supporting Evidence: PMID:28842490 mammalian cis-PT is a heteromer consisting of NgBR (Nus1) and hCIT (dehydrodolichol diphosphate synthase) subunits |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-4755545 | ACCEPT | Summary: Correct ER membrane localization asserted by Reactome, consistent with experimental evidence. Redundant with the IDA (PMID:14652022) but records the gene's own correct compartment; accepted. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-4419978 | ACCEPT | Summary: Correct ER membrane localization asserted by Reactome (DHDDS:NUS1 elongation reaction), consistent with the experimentally determined location. Accepted. Supporting Evidence: file:human/DHDDS/DHDDS-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:15110773 In vivo interaction between the human dehydrodolichyl diphos... | KEEP AS NON CORE | Summary: Yeast two-hybrid (confirmed by co-IP) interaction of human dehydrodolichyl diphosphate synthase with Niemann-Pick C2 protein (NPC2, UniProtKB:P61916). This is a genuine but ancillary interaction linked to cholesterol trafficking rather than the core catalytic function; bare "protein binding" is uninformative. Kept as a non-core interaction (experimental IPI, not removed). Supporting Evidence: PMID:15110773 We identified Niemann-Pick Type C2 protein (NPC2) to show a specific interaction with human DedolPP synthase |
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