KCS1 (YDR017C) encodes the sole Saccharomyces cerevisiae inositol hexakisphosphate kinase (IP6K; EC 2.7.4.21), a member of the inositol phosphokinase (IPK) family related to IPMK/Arg82. Kcs1 pyrophosphorylates the 5-position of IP6 to produce 5-diphosphoinositol pentakisphosphate (5-IP7), converts IP5 to PP-IP4, and converts the Vip1 product 1-IP7 to 1,5-IP8. Kcs1 accounts for most cellular inositol pyrophosphate synthesis; kcs1 cells have fragmented vacuoles, cell-wall and salt stress defects, low polyphosphate, derepressed PHO genes, longer telomeres and, through loss of INO1 transcription, inositol auxotrophy. Besides the kinase domain, Kcs1 carries a leucine heptad-repeat (bZIP-like) region needed for vacuole biogenesis and INO1 expression. Kcs1 is mainly cytoplasmic. Inositol pyrophosphates made by Kcs1p are also needed for normal RNA polymerase I-mediated rRNA transcription and ribosome biogenesis. Kcs1p is itself regulated by the AMP-activated kinase Snf1p, which phosphorylates it at Ser537 and Ser646; this lowers InsP7 levels and supports pseudohyphal and invasive growth.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000824 inositol-1,4,5,6-tetrakisphosphate 3-kinase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA from PTN000963723 seeded only by ARG82 (SGD:S000002580) for inositol-1,4,5,6-tetrakisphosphate 3-kinase activity. This is the IPMK (Arg82) activity. Kcs1 is an IP6 kinase specialised for IP6/IP5 pyrophosphorylation; overexpressed Kcs1 can act on a wider range of substrates and partially bypass arg82, but at native levels it does not provide 3-kinase activity (arg82 cells accumulate IP3 and lose IP6). Over-propagation across the IPMK/IP6K split. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: SGD:S000002580 · ARG82 (Ipk2/IPMK), S. cerevisiae SUPPORTS SOURCE BUT NOT TARGET The only experimental donor is the yeast IPMK paralog Arg82, which genuinely has IP3/IP4 3-/6-kinase activity. Kcs1 belongs to the IP6K subfamily of the shared IPK fold and does not substitute for Arg82 in vivo (arg82 cells accumulate IP3 170-fold despite having Kcs1). PANTHER:PTN000963723 · PANTHER node joining IPMK and IP6K subfamilies UNRESOLVED The IPMK-specific 3-kinase specificity appears to be placed at a node that also covers IP6Ks. Supporting Evidence: PMID:10827188 The mammalian type 2 kinase and the yeast kinase are more specialized for the phosphorylation of InsP(6). PMID:11956213 This was due, in part, to the ability of Kcs1p to phosphorylate a wider range of substrates than previously appreciated. PMID:10683435 increased cellular [InsP(3)] 170-fold and decreased [InsP(6)] 100-fold, indicating reduced phosphorylation of InsP(3) to InsP(6) |
| GO:0000827 inositol-1,3,4,5,6-pentakisphosphate kinase activity | IDA PMID:10827188 The inositol hexakisphosphate kinase family. Catalytic flexi... | ACCEPT | Summary: IDA from Saiardi et al. 2000: yeast and mammalian IP6 kinases also phosphorylate InsP5 to PP-InsP4 (diphosphoinositol tetrakisphosphate), matching the GO definition (IP5 + ATP -> diphospho-IP4). Ye et al. 2013 show this IP5-derived route is physiologically important for INO1 expression. Supporting Evidence: PMID:10827188 inositol pentakisphosphate (InsP(5)) was phosphorylated to diphosphoinositol tetrakisphosphate (PP-InsP(4)) PMID:23824185 The Kcs1-catalyzed production of inositol pyrophosphates from inositol pentakisphosphate but not inositol hexakisphosphate is indispensable for optimal INO1 transcription. |
| GO:0000828 inositol hexakisphosphate kinase activity | IDA PMID:10574768 Synthesis of diphosphoinositol pentakisphosphate by a newly ... | ACCEPT | Summary: IDA from Saiardi et al. 1999: cloning and assay of the yeast InsP6 kinase (Kcs1) converting IP6 to PP-InsP5. Core activity. Supporting Evidence: PMID:10574768 Here, we report the cloning of two mammalian InsP(6) kinases and a yeast InsP(6) kinase. |
| GO:0000828 inositol hexakisphosphate kinase activity | IDA PMID:11956213 In Saccharomyces cerevisiae, the inositol polyphosphate kina... | ACCEPT | Summary: IDA from Dubois et al. 2002: a kinase-dead kcs1 mutant fails to make diphosphoinositol polyphosphates, tying IP6 kinase activity to Kcs1. Supporting Evidence: PMID:11956213 transformed with a specifically "kinase-dead" kcs1p mutant did not synthesize diphosphoinositol polyphosphates |
| GO:0000828 inositol hexakisphosphate kinase activity | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways PWY3O-402 (phytate + ATP -> 5-PP-IP5, EC 2.7.4.21). Correct. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt Reaction=1D-myo-inositol hexakisphosphate + ATP = 5-diphospho-1D-myo- |
| GO:0000829 diphosphoinositol pentakisphosphate kinase activity | IDA PMID:11956213 In Saccharomyces cerevisiae, the inositol polyphosphate kina... | ACCEPT | Summary: IDA from Dubois et al. 2002 for diphosphoinositol pentakisphosphate kinase activity (PP-IP5 -> [PP]2-IP4). Kcs1 phosphorylates a broader substrate range than initially thought, and UniProt records Kcs1 converting 1-PP-InsP5 (the Vip1 product) to 1,5-[PP]2-InsP4 (IP8). Accepted, deferring to the curator on full-text details. Supporting Evidence: PMID:11956213 This was due, in part, to the ability of Kcs1p to phosphorylate a wider range of substrates than previously appreciated. file:yeast/KCS1/KCS1-uniprot.txt Reaction=1-diphospho-1D-myo-inositol 2,3,4,5,6-pentakisphosphate + ATP |
| GO:0000832 inositol hexakisphosphate 5-kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA (RHEA:12793) for inositol hexakisphosphate 5-kinase activity. This is the most precise description of Kcs1's main activity: pyrophosphorylation of the 5-position of IP6 to give 5-PP-InsP5 (5-IP7). Core. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt Reaction=1D-myo-inositol hexakisphosphate + ATP = 5-diphospho-1D-myo- PMID:23824185 Deletion of KCS1, which blocks synthesis of inositol pyrophosphates on the 5-hydroxyl of the inositol ring, causes inositol auxotrophy and decreased intracellular inositol and phosphatidylinositol. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA (is_active_in nucleus) from PTN000963625 with donors mostly mammalian IPMK/IP6K proteins and ARG82. Mammalian IP6K1/IP6K2 and yeast Arg82 are partly nuclear, but the only direct yeast data (GFP collection) score Kcs1 as cytoplasmic. Kcs1 products influence nuclear processes (PHO, INO1 transcription, telomere length), which may be achieved by diffusible PP-InsPs. No direct evidence for or against a nuclear pool of Kcs1 is available here. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14562095}. |
| GO:0005737 cytoplasm | HDA PMID:14562095 Global analysis of protein localization in budding yeast. | ACCEPT | Summary: HDA from the genome-wide GFP localization study (cytoplasm). Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14562095}. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (is_active_in cytoplasm) from PTN000963625; consistent with yeast GFP data. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14562095}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (SL-0086), from the GFP study. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14562095}. |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways PWY3O-402 placing IP6 kinase reactions in the cytosol; consistent with GFP data. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14562095}. |
| GO:0008440 inositol-1,4,5-trisphosphate 3-kinase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA from PTN000963723 seeded only by ARG82 for inositol-1,4,5-trisphosphate 3-kinase activity. Same over-propagation as the IP4 3-kinase IBA: IP3 3-kinase is an Arg82/IPMK activity, and Kcs1 at native levels does not phosphorylate IP3 (arg82 cells accumulate IP3 170-fold). Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: SGD:S000002580 · ARG82 (Ipk2/IPMK), S. cerevisiae SUPPORTS SOURCE BUT NOT TARGET The only experimental donor is the yeast IPMK paralog Arg82, which genuinely has IP3/IP4 3-/6-kinase activity. Kcs1 belongs to the IP6K subfamily of the shared IPK fold and does not substitute for Arg82 in vivo (arg82 cells accumulate IP3 170-fold despite having Kcs1). PANTHER:PTN000963723 · PANTHER node joining IPMK and IP6K subfamilies UNRESOLVED The IPMK-specific 3-kinase specificity appears to be placed at a node that also covers IP6Ks. Supporting Evidence: PMID:10683435 increased cellular [InsP(3)] 170-fold and decreased [InsP(6)] 100-fold, indicating reduced phosphorylation of InsP(3) to InsP(6) PMID:10827188 The mammalian type 2 kinase and the yeast kinase are more specialized for the phosphorylation of InsP(6). |
| GO:0010919 regulation of inositol phosphate biosynthetic process | IMP PMID:23824185 Regulation of inositol metabolism is fine-tuned by inositol ... | MODIFY | Summary: IMP from Ye et al. 2013. kcs1 cells become inositol auxotrophs because INO1 transcription collapses; the paper shows Kcs1-derived inositol pyrophosphates regulate de novo inositol (and hence PI) synthesis via INO1 expression, not the biosynthesis of inositol phosphates. The regulated process is inositol biosynthesis. Proposed replacements: regulation of inositol biosynthetic process Supporting Evidence: PMID:23824185 Deletion of KCS1, which blocks synthesis of inositol pyrophosphates on the 5-hydroxyl of the inositol ring, causes inositol auxotrophy and decreased intracellular inositol and phosphatidylinositol. PMID:23824185 These defects are caused by a profound decrease in transcription of INO1 |
| GO:0016301 kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: IEA from InterPro IPR005522 (inositol polyphosphate kinase family) to kinase activity. Too general; the specific activity is IP6 5-kinase (pyrophosphorylation of IP6). Proposed replacements: inositol hexakisphosphate 5-kinase activity Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt Reaction=1D-myo-inositol hexakisphosphate + ATP = 5-diphospho-1D-myo- |
| GO:0030643 intracellular phosphate ion homeostasis | IMP PMID:15866881 Plc1p, Arg82p, and Kcs1p, enzymes involved in inositol pyrop... | KEEP AS NON CORE | Summary: IMP (acts_upstream_of_or_within) from Auesukaree et al. 2005: kcs1 deletion constitutively derepresses PHO5 and reduces polyphosphate, and KCS1 overexpression suppresses PHO5. Kcs1 contributes to phosphate homeostasis through its PP-InsP products acting on the PHO pathway; a genuine but downstream/regulatory role. Supporting Evidence: PMID:15866881 We found that disruptants of PLC1, ARG82, and KCS1, which are involved in the synthesis of inositol polyphosphate, and ADK1, which encodes adenylate kinase, constitutively express PHO5. PMID:15866881 had significantly reduced intracellular polyphosphate levels |
| GO:0032958 inositol phosphate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER PTN004357288 (donors include ARG82 and KCS1 itself, SGD:S000002424, plus plant, fly and mouse IPK-family members) for inositol phosphate biosynthetic process. Kcs1 synthesises inositol pyrophosphates (IP7, PP-IP4, IP8). Supporting Evidence: PMID:10574768 Here, we report the cloning of two mammalian InsP(6) kinases and a yeast InsP(6) kinase. |
| GO:0032958 inositol phosphate biosynthetic process | IDA PMID:10574768 Synthesis of diphosphoinositol pentakisphosphate by a newly ... | ACCEPT | Summary: IDA from Saiardi et al. 1999: Kcs1 synthesises PP-InsP5 from IP6. Supporting Evidence: PMID:10574768 Here, we report the cloning of two mammalian InsP(6) kinases and a yeast InsP(6) kinase. |
| GO:0032958 inositol phosphate biosynthetic process | IDA PMID:17412958 A conserved family of enzymes that phosphorylate inositol he... | ACCEPT | Summary: IDA from Mulugu et al. 2007 (Vip1 discovery paper); the PP-InsP synthesis assays include Kcs1 as the established IP6 kinase. Accepted, deferring to the curator on full-text details. Supporting Evidence: PMID:17412958 Vip1 and Asp1 acted as enzymes that encode inositol hexakisphosphate (IP6) and inositol heptakisphosphate (IP7) kinase activities. |
| GO:0032958 inositol phosphate biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro IPR005522. Correct for this IPK-family enzyme. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt SIMILARITY: Belongs to the inositol phosphokinase (IPK) family. |
| GO:0032958 inositol phosphate biosynthetic process | IMP PMID:11956213 In Saccharomyces cerevisiae, the inositol polyphosphate kina... | ACCEPT | Summary: IMP from Dubois et al. 2002: kinase-dead kcs1 does not make diphosphoinositol polyphosphates. Supporting Evidence: PMID:11956213 transformed with a specifically "kinase-dead" kcs1p mutant did not synthesize diphosphoinositol polyphosphates |
| GO:0032958 inositol phosphate biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways PWY3O-402. Correct. Supporting Evidence: file:yeast/KCS1/KCS1-uniprot.txt Reaction=1D-myo-inositol hexakisphosphate + ATP = 5-diphospho-1D-myo- |
| GO:0046854 phosphatidylinositol phosphate biosynthetic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA from PTN000274018 (donors ARG82, human ITPKA/ITPKB, IPMK) for phosphatidylinositol phosphate biosynthetic process. The lipid (PI 3-kinase) activity is specific to IPMK (Arg82); no lipid kinase activity has been reported for Kcs1 or other IP6Ks, which act on soluble IP5/IP6/IP7. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE WRONG ORTHOLOG OR PARALOG Sources checked: SGD:S000002580 · ARG82 (IPMK) SUPPORTS SOURCE BUT NOT TARGET Arg82/IPMK lipid 3-kinase activity (Resnick et al. 2005) does not extend to the IP6K subfamily. Supporting Evidence: PMID:10827188 The mammalian type 2 kinase and the yeast kinase are more specialized for the phosphorylation of InsP(6). |
| GO:0120517 inositol pentakisphosphate kinase activity | RCA GO_REF:0000123 | MODIFY | Summary: RCA from YeastPathways PWY3O-402 for the reaction ATP + Ins(1,3,4,5,6)P5 -> diphospho-IP4. The GO term chosen (inositol pentakisphosphate kinase activity) is defined as IP5 -> IP6, which is the Ipk1 reaction, not Kcs1's. Kcs1 pyrophosphorylates IP5 to PP-IP4, which is GO:0000827. Proposed replacements: inositol-1,3,4,5,6-pentakisphosphate kinase activity Supporting Evidence: PMID:10827188 inositol pentakisphosphate (InsP(5)) was phosphorylated to diphosphoinositol tetrakisphosphate (PP-InsP(4)) |
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Download this section (compressed HTML)Q: What is the molecular function of the Kcs1 leucine heptad-repeat (bZIP-like) region required for vacuole biogenesis and INO1 expression, and does it mediate protein interactions or localization?
Q: Is there a nuclear pool of Kcs1, or do its PP-InsP products diffuse into the nucleus to regulate PHO and INO1 transcription and telomere length?
Experiment: Separate catalytic and non-catalytic roles by expressing kinase-dead Kcs1 and a leucine-zipper deletion in kcs1 cells, measuring IP7/IP8 isomers, INO1 transcription and vacuole morphology; localize endogenously tagged Kcs1 under phosphate and inositol limitation.
Inositol hexakisphosphate (IP6) and inositol heptakisphosphate (IP7) kinase; generation of high energy inositol pyrophosphates by Kcs1p is required for many processes such as vacuolar biogenesis, stress response, RNA polymerase I-mediated rRNA transcription and telomere maintenance; phosphorylated by the AMPK Snf1p, leading to reduced levels of pyrophosphorylated IP7, increased filamentous and invasive growth and increased cell elongation
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