Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan.
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Zebrafish ispd knockdown reduces glycosylated (IIH6-reactive) alpha-dystroglycan, reproducing the diagnostic feature of Walker-Warburg syndrome.
"Compared with control embryos, glycosylated αDG was reduced in ispd MO1-injected zebrafish embryos"
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Both ispd morpholinos cause hydrocephalus, incomplete brain folding and reduced eye size by 48 hpf.
"High doses of ispd MO1 (7 ng) caused hydrocephalus and incomplete brain folding in 82% of embryos (n=88) by 48 hours post fertilization (h.p.f.)"
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Loss of Ispd compromises sarcolemma integrity before muscle fiber degeneration, independently of laminin and dystrophin localization.
"loss of Ispd function in zebrafish results in αDG hypoglycosylation and compromised sarcolemma integrity, preceding muscle fiber degeneration"
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Sub-effective ispd morpholino doses synergize with fktn and fkrp morpholinos, placing ispd in the same alpha-dystroglycan glycosylation pathway.
"These results support a cooperative interaction between ispd and fktn/fkrp in αDG glycosylation."
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The MEP isoprenoid pathway in which bacterial IspD acts is absent from vertebrates, so the vertebrate enzyme cannot function in isoprenoid biosynthesis.
"In plants, protozoa and some bacteria, ISPD belongs to the non-mevalonate isoprenoid biosynthesis (MEP) pathway, which is absent in vertebrates"
ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan.
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Recombinant mammalian ISPD is a CDP-ribitol pyrophosphorylase, with D-ribitol 5-phosphate as the preferred substrate.
"However, we clearly observed a CDP-ribitol pyrophosphorylase activity (Fig. 1b)."
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ISPD has no activity on the MEP-pathway substrate 2-C-methyl-D-erythritol 4-phosphate, excluding an isoprenoid-biosynthesis role.
"No activity was observed in the presence of UTP, or in the presence of CTP and 2-C-methyl-D-erythritol-4-P, which is the substrate utilized in related enzymes in the mevalonate pathway."
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FKTN and FKRP use CDP-ribitol made by ISPD to add ribitol phosphate to alpha-dystroglycan, defining ISPD's step in O-mannosyl glycan biosynthesis.
"both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan"
Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation.
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Human ISPD is cytosolic and has cytidyltransferase activity toward pentose phosphates including ribitol 5-phosphate.
"Functional studies demonstrated cytosolic localization of hISPD, and cytidyltransferase activity toward pentose phosphates, including ribulose 5-phosphate, ribose 5-phosphate, and ribitol 5-phosphate."
UniProtKB entry A0JPF9 for Danio rerio crppa
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UniProt describes CRPPA as a cytosolic cytidylyltransferase that forms CDP-ribitol for protein O-linked mannosylation.
"Catalyzes the formation of CDP-ribitol"
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The catalytic activity recorded on the entry (by similarity to human ISPD) is the RHEA:12456 reaction.
"Reaction=D-ribitol 5-phosphate + CTP + H(+) = CDP-L-ribitol + diphosphate"
Falcon deep research report for Danio rerio crppa (UniProt A0JPF9)
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The report identifies zebrafish crppa (synonym ispd, UniProt A0JPF9) as the vertebrate ISPD/CRPPA ortholog, a D-ribitol-5-phosphate cytidylyltransferase, not a microbial isoprenoid enzyme.
"a **D-ribitol-5-phosphate cytidylyltransferase / CDP-L-ribitol pyrophosphorylase A (CRPPA)**"
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Zebrafish ispd has two splice isoforms with different N-termini but a shared conserved ISPD domain.
"two splice isoforms with different N-termini but a shared conserved ISPD domain"