GND1 encodes 6-phosphogluconate dehydrogenase (decarboxylating) (EC 1.1.1.44), the NADP+-dependent enzyme of the oxidative pentose phosphate pathway (oxPPP). It catalyses 6-phospho-D-gluconate + NADP+ -> D-ribulose 5-phosphate + CO2 + NADPH, the second NADPH-generating step of the oxPPP, and feeds ribulose 5-phosphate into the non-oxidative branch for nucleotide and pentose-sugar interconversions. The enzyme is a homodimer of the 6PGDH family whose N-terminal coenzyme-binding domain carries the Gly-X-Ala-X-Met-Gly fingerprint and the Asn-Arg-Thr 2'-phosphate-binding motif that characterise NADP+-specific 6PGDHs, in contrast to the NAD+-preferring bacterial forms. In Candida albicans, Gnd1 is predominantly cytosolic, but a minor peroxisomal pool (about 5% of the protein) is generated by alternative splicing of an intron that encodes an in-frame PTS2; import of this isoform depends on the PTS2 receptor Pex7 and is most evident under peroxisome-inducing conditions such as growth on oleate. Iron limitation up-regulates GND1 together with ZWF1 as part of a metabolic remodelling that increases oxPPP NADPH production for redox defence.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004616 phosphogluconate dehydrogenase (decarboxylating) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function: Gnd1 is the NADP+-dependent 6-phosphogluconate dehydrogenase (EC 1.1.1.44) catalysing 6-phospho-D-gluconate + NADP+ -> D-ribulose 5-phosphate + CO2 + NADPH, the second NADPH-generating step of the oxidative PPP. The term is defined with NADP+ as the acceptor; this cofactor specificity is the correct one for the C. albicans enzyme: the coenzyme-binding domain carries the Gly-X-Ala-X-Met-Gly fingerprint and the Asn-Arg-Thr 2'-phosphate motif that define NADP+ specificity in 6PGDHs, and lacks the Asp-Arg-Asp motif of NAD+-preferring bacterial enzymes. Oxidative-PPP NADPH production attributable to Zwf1 plus Gnd1 has been measured in C. albicans lysates with NADP+ as the acceptor. Reason: Well-supported core catalytic function at the right level of cofactor specificity. The phylogenetic inference is consistent with the UniProt family/EC assignment, with the conserved NADP+-specificity determinants in the sequence, and with the NADP+-dependent oxidative-PPP activity attributable to Zwf1 plus Gnd1 measured in C. albicans extracts. Supporting Evidence: PMID:35234135 6-Phosphogluconate dehydrogenase (6PGDH; EC 1.1.1.44) catalyses the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate in the context of the oxidative part of the pentose phosphate pathway. PMID:35234135 highlighted the role of Asn32, Arg33 and Thr34 in the turn between Ξ²b and Ξ±b in interacting with the 2β²-phosphate mainly by hydrogen bonds and defining NADP+ specificity file:CANAL/GND1/GND1-bioinformatics/RESULTS.md Verdict (from `results.json`): NADP+-specific determinants present (Asn-Arg-Thr); NAD+-type Asp-Arg-Asp absent. PMID:40183578 Since ZWF1 catalysis provides the 6-phosphogluconate substrate for GND1 (see Fig. 6A), the NADPH formed reflects activity from both enzymes |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IBA GO_REF:0000033 | ACCEPT | Summary: Gnd1 is one of the two NADPH-producing dehydrogenases of the oxidative branch of the PPP in C. albicans, acting downstream of Zwf1; the genes for both are induced together under iron starvation with a matching increase in oxidative-PPP NADPH production. Reason: Direct pathway placement in C. albicans supports the oxidative-branch term as the core process. Supporting Evidence: PMID:22094058 NADPH is produced by the two dehydrogenases in the oxidative branch of the PPP: glucose-6-phosphate dehydrogenase (Zwf1) and 6-phosphogluconate dehydrogenase (Gnd1). PMID:40183578 the NADPH-producing ZWF1 and GND1 genes of oxidative PPP are markedly induced in Fe-starved C. albicans WT and sef1 |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: The majority of Gnd1 is cytosolic by subcellular fractionation and fluorescence microscopy; this is the compartment of the core oxidative PPP activity. Reason: Consistent with the direct localization data for the C. albicans protein and with 6PGDH being mainly cytosolic across species. Supporting Evidence: PMID:22094058 By subcellular fractionation and fluorescence microscopy, we show that both enzymes have a dual localization in which the majority is cytosolic, but a small fraction is peroxisome associated. PMID:35234135 6PGDH is mainly cytosolic, although isoforms are present in organelles such as peroxisomes and chloroplasts |
| GO:0050661 NADP binding | IBA GO_REF:0000033 | ACCEPT | Summary: NADP+ is the coenzyme of the catalysed reaction. The UniProt record annotates NADP(+) binding features at residues 13-18, 36-38, 78-80 and 106, and the first two coincide with the conserved Gly-X-Ala-X-Met-Gly fingerprint and Asn-Arg-Thr 2'-phosphate-binding motif that confer NADP+ over NAD+ specificity. Reason: Binding of the coenzyme is intrinsic to the NADP+-dependent dehydrogenase activity and the specificity determinants are conserved in the C. albicans sequence. Supporting Evidence: file:CANAL/GND1/GND1-bioinformatics/RESULTS.md Both NADP+-specificity determinants of the sheep enzyme are conserved in C. albicans Gnd1 at a constant offset of +4 residues, and both coincide exactly with the PIRSR-derived NADP(+) binding features in the UniProt record (13..18 and 36..38). PMID:35234135 Mutagenesis of the conserved arginine and asparagine in Lactococcus lactis and Gluconobacter oxydans 6PGDH demonstrated their role in specificity for NADP+ over NAD+, while showing that aspartate, which is present in NAD+-dehydrogenases in place of the asparagine, hinders placement of the 2 |
| GO:0004616 phosphogluconate dehydrogenase (decarboxylating) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Same NADP+-dependent 6-phosphogluconate dehydrogenase activity as the IBA annotation, here from the combined automated (InterPro/UniRule) mapping; see the IBA entry for the cofactor-specificity assessment. Reason: Consistent with the family/EC assignment and with the conserved NADP+-specificity motifs. The C. albicans lysate assay starts from glucose 6-phosphate and reports NADPH from Zwf1 plus Gnd1 together, so it establishes that the pathway runs NADP+-dependently rather than that Gnd1 individually cannot use NAD+; the cofactor call rests on the sequence determinants. Supporting Evidence: file:CANAL/GND1/GND1-bioinformatics/RESULTS.md Verdict (from `results.json`): NADP+-specific determinants present (Asn-Arg-Thr); NAD+-type Asp-Arg-Asp absent. PMID:40183578 Since ZWF1 catalysis provides the 6-phosphogluconate substrate for GND1 (see Fig. 6A), the NADPH formed reflects activity from both enzymes |
| GO:0006098 pentose-phosphate shunt | IEA GO_REF:0000120 | ACCEPT | Summary: Parent-level pathway term for the oxidative-branch annotation; Gnd1 is an oxidative-PPP enzyme so the general term is correct, if less specific than GO:0009051. Reason: Correct but less specific than the oxidative-branch term that is also annotated; acceptable for an electronic annotation. Criterion for the two keyword/IEA-derived parents on this gene - a contentful pathway term that is the direct parent of an annotated term (this one) is accepted, whereas a near-root grouping term with no pathway content (GO:0016491) is marked over-annotated. Supporting Evidence: PMID:40183578 PPP has both an oxidative component where ZWF1 and GND1 generate NADPH for oxidative stress protection |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Oxidoreductase activity is a high-level parent of GO:0004616 (phosphogluconate dehydrogenase (decarboxylating) activity), which is already annotated to GND1 from the UniProt "Oxidoreductase" keyword. The generic grouping term adds no information beyond the specific catalytic activity. Reason: Subsumed by the more specific and already-annotated GO:0004616; the keyword-derived parent term conveys nothing the specific term does not. Contrast GO:0006098, also a keyword/IEA-derived parent, which is accepted because it is a contentful pathway term and the direct parent of the annotated oxidative-branch term, whereas oxidoreductase activity is a near-root grouping term. |
| GO:0019521 D-gluconate metabolic process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Substrate over-generalisation from a keyword mapping. This annotation derives from the UniProt keyword "Gluconate utilization" (ARBA/RuleBase), which UniProt applies broadly to 6-phosphogluconate-metabolising enzymes irrespective of lineage or pathway context: on this entry it is attached by an automated family rule (ECO:0000256|ARBA:ARBA00023064, RuleBase RU000485) that travels with 6PGDH sequence membership, and the same keyword is carried by the human enzyme PGD and by the bacterial ortholog PSEPK gntZ alike. The keyword therefore does not by itself establish that free D-gluconate is metabolised. The substrate of Gnd1 is 6-phospho-D-gluconate, a distinct chemical entity from D-gluconate, and in the yeast oxidative PPP that substrate is supplied by Zwf1 and 6-phosphogluconolactonase from glucose 6-phosphate rather than from exogenous gluconate. No evidence that C. albicans routes free D-gluconate through Gnd1 was retrieved. Reason: GO:0019521 is pathway-scoped (reactions and pathways involving D-gluconate), so the discriminating question is whether C. albicans routes free D-gluconate into the PPP - not merely which substrate the enzyme binds. No evidence that it does was retrieved; the file asks this directly under suggested_questions and proposes the gluconate growth / gluconokinase assay that would settle it under suggested_experiments. GO:0009051 already captures the pathway the enzyme is actually known to act in. Not demonstrably false, so flagged as over-annotation rather than removed. Note a deliberate divergence from the human ortholog review (genes/human/PGD/PGD-ai-review.yaml), which retains the identical keyword-derived annotation as KEEP_AS_NON_CORE. Both reviews agree the term is a keyword-driven generalisation of the substrate; they differ only in whether that generalisation is recorded as acceptable-but-peripheral or as over-annotation. Supporting Evidence: PMID:40183578 Since ZWF1 catalysis provides the 6-phosphogluconate substrate for GND1 (see Fig. 6A), the NADPH formed reflects activity from both enzymes |
| GO:0050661 NADP binding | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic counterpart of the IBA NADP binding annotation; the NADP+ coenzyme is bound through the conserved Gly-X-Ala-X-Met-Gly fingerprint and Asn-Arg-Thr 2'-phosphate motif, matching the UniProt NADP(+) binding features. Reason: Binding of the coenzyme is intrinsic to the NADP+-dependent activity; the specificity determinants are conserved in the C. albicans sequence. Supporting Evidence: file:CANAL/GND1/GND1-bioinformatics/RESULTS.md Verdict (from `results.json`): NADP+-specific determinants present (Asn-Arg-Thr); NAD+-type Asp-Arg-Asp absent. |
| GO:0009051 pentose-phosphate shunt, oxidative branch | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic counterpart of the IBA oxidative-branch annotation; Gnd1 is one of the two NADPH-producing dehydrogenases of the oxidative PPP in C. albicans. Reason: Direct pathway placement in C. albicans supports the oxidative-branch term. Supporting Evidence: PMID:22094058 NADPH is produced by the two dehydrogenases in the oxidative branch of the PPP: glucose-6-phosphate dehydrogenase (Zwf1) and 6-phosphogluconate dehydrogenase (Gnd1). |
| GO:0062040 fungal biofilm matrix | IDA PMID:27609602 Null mutants of Candida albicans for cell-wall-related genes... | KEEP AS NON CORE | Summary: Gnd1 was detected by 2-DE/mass spectrometry among the proteins (including oxidoreductases) recovered from the C. albicans biofilm extracellular matrix. This is a context-dependent proteomic detection of an abundant metabolic enzyme rather than evidence of a dedicated structural role in the matrix. The quotable abstract establishes only that the study is a matrix proteomic survey; the Gnd1-specific detection is in the full text, which is not in the cache, so the IDA is taken on the curator's reading. Reason: Detection in a biofilm-matrix proteomic survey is context-dependent and likely reflects the high abundance of this cytosolic metabolic enzyme rather than a core matrix function; kept as non-core. Supporting Evidence: PMID:27609602 Proteomic analysis led to the identification of 131 polypeptides, corresponding to 86 different protein species |
| GO:0005777 peroxisome | IDA PMID:22094058 Alternative splicing directs dual localization of Candida al... | KEEP AS NON CORE | Summary: A minor Gnd1 isoform bearing an N-terminal PTS2, generated by alternative splicing of the GND1 intron, is imported into peroxisomes; subcellular fractionation shows only a small fraction (about 5%) is peroxisome-associated while the majority is cytosolic. This is a real but condition-dependent minor pool, proposed to supply NADPH for detoxifying ROS produced during fatty-acid degradation. Reason: Peroxisomal localization reflects a minor PTS2-targeted splice isoform rather than the predominant cytosolic activity; kept as non-core. Supporting Evidence: PMID:22094058 By subcellular fractionation and fluorescence microscopy, we show that both enzymes have a dual localization in which the majority is cytosolic, but a small fraction is peroxisome associated. PMID:22094058 dual targeting of Gnd1 is directed by alternative splicing resulting in two Gnd1 isoforms, one without targeting signals localized to the cytosol and one with an N-terminal PTS2 targeted to peroxisomes PMID:34065948 approximately 10% and 5% of the proteins, respectively, were localized in peroxisomes, providing a means for detoxification of ROS produced during fatty acid degradation file:CANAL/GND1/GND1-deep-research-falcon.md predominantly cytosolic; a minor peroxisomal isoform is produced via alternative splicing generating a PTS2-containing form imported via Pex7, particularly evident under peroxisome-inducing conditions (e.g., oleate) |
| GO:0005829 cytosol | IDA PMID:22094058 Alternative splicing directs dual localization of Candida al... | ACCEPT | Summary: Subcellular fractionation and fluorescence microscopy show that the majority of Gnd1 is cytosolic. This is the predominant localization and the site of its core oxidative PPP NADPH-generating activity. Reason: Cytosol is the predominant localization of Gnd1 and the compartment where its core oxidative PPP function occurs. Supporting Evidence: PMID:22094058 By subcellular fractionation and fluorescence microscopy, we show that both enzymes have a dual localization in which the majority is cytosolic, but a small fraction is peroxisome associated. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Has the coenzyme preference of purified C. albicans Gnd1 been measured directly (NAD+ versus NADP+ kinetics), or is NADP+ dependence inferred only from assay conditions and sequence motifs?
Suggested experts: Distel B, Strijbis K
Q: Does C. albicans assimilate exogenous D-gluconate through a gluconokinase feeding 6-phosphogluconate to Gnd1, which would justify the keyword-derived D-gluconate metabolic process annotation?
Experiment: Purify recombinant C. albicans Gnd1 and compare kcat/Km with NADP+ and NAD+ as acceptor, including the N36D (Asn-Arg-Thr to Asp-Arg-Thr) variant.
Hypothesis: The wild-type enzyme is strongly NADP+-specific and the Asn36 to Asp substitution shifts preference toward NAD+, as reported for bacterial 6PGDHs.
Type: Enzyme kinetics
Experiment: Test growth of wild-type and gnd1 mutant C. albicans on D-gluconate as sole carbon source and assay gluconokinase activity in extracts.
Hypothesis: C. albicans does not catabolise free D-gluconate via Gnd1, so the D-gluconate metabolic process annotation is a keyword artefact.
Type: Physiology
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)