Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The serotype-specific, 5.9-kb region II of the Haemophilus influenzae type a capsulation locus was sequenced and found to contain four open reading frames termed acs1 to acs4. Acs1 was 96% identical to H. influenzae type b Orf1, previously shown to have CDP-ribitol pyrophosphorylase activity (J. Van Eldere, L. Brophy, B. Loynds, P. Celis, I. Hancock, S. Carman, J. S. Kroll, and E. R. Moxon, Mol. Microbiol. 15:107-118, 1995). Low but significant homology to other pyrophosphorylases was only detected in the N-terminal part of Acs1, whereas the C-terminal part was homologous to several short-chain dehydrogenases/reductases, suggesting that Acs1 might be a bifunctional enzyme. To test this hypothesis, acs1 was cloned in an expression vector and overexpressed in Escherichia coli. Cells expressing this protein displayed both ribitol 5-phosphate dehydrogenase and CDP-ribitol pyrophosphorylase activities, whereas these activities were not detectable in control cells. Acs1 was purified to near homogeneity and found to copurify with ribitol 5-phosphate dehydrogenase and CDP-ribitol pyrophosphorylase activities. These had superimposable elution profiles from DEAE-Sepharose and Blue-Sepharose columns. The dehydrogenase activity was specific for ribulose 5-phosphate and NADPH in one direction and for ribitol 5-phosphate and NADP+ in the other direction and was markedly stimulated by CTP. The pyrophosphorylase showed activity with CTP and ribitol 5-phosphate or arabitol 5-phosphate. We conclude that acs1 encodes a bifunctional enzyme that converts ribulose 5-phosphate into ribitol 5-phosphate and further into CDP-ribitol, which is the activated precursor form for incorporation of ribitol 5-phosphate into the H. influenzae type a capsular polysaccharide.
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PMID:acs1 of Haemophilus influenzae type a capsulation locus region II encodes a bifunctional ribulose 5-phosphate reductase- CDP-ribitol pyrophosphorylase. 1009 75

The homeodomain transcription factor CDP/cut contains four separate DNA binding domains and interacts with large segments of DNA. Thus, CDP/cut has the potential to function as an architectural protein and perhaps to support modifications in chromatin structure and nucleosomal organization. To begin to examine the ability of CDP/cut to interact with chromatin, we analyzed binding of CDP/cut to the histone H4 gene promoter (-90 to +75) reconstituted into nucleosome cores. The -90 to +75 region encompasses the cell cycle regulatory element (Site II) that controls histone H4 gene transcription, a CDP/cut binding site and a nuclease hypersensitive region. Using electrophoretic mobility shift assays and DNase I footprinting experiments, we show that CDP/cut specifically interacts with its recognition motif in a nucleosomal context without displacing the nucleosome core. The competency of CDP/cut to interact with nucleosomes suggests that this transcription factor may facilitate chromatin remodeling in response to cell cycle regulatory and/or developmental cues.
Mol Biol Rep 1999 Aug
PMID:The homeodomain transcription factor CDP/cut interacts with the cell cycle regulatory element of histone H4 genes packaged into nucleosomes. 1053 14

It is believed that phosphatidylinositol (PI) metabolism plays a central role in signalling pathways in both animals and higher plants. PI is synthesized from CDP-diacylglycerol (CDP-DG) and myo-inositol by phosphatidylinositol synthase (PI synthase, EC 2.7.8.11). Here we report the identification of a plant cDNA (AtPIS1) encoding a 26 kDa PI synthase from Arabidopsis thaliana. The plant enzyme as deduced from its cDNA sequence shares 35-41% identical amino acids with PI synthases from Saccharomyces cerevisiae and mammals. AtPIS1 functionally complements a mutant of S. cerevisiae with a lesion in PI synthase, and recombinant AtPIS1 protein present in yeast membranes strongly depends on the two principal substrates, myo-inositol and CDP-DG, and requires Mg2+ ions for full activity.
Plant Mol Biol 2000 Mar
PMID:Cloning of Arabidopsis thaliana phosphatidylinositol synthase and functional expression in the yeast pis mutant. 1080 47

Crystal structures of carbon monoxide dehydrogenase (CODH), a seleno-molybdo-iron-sulfur flavoprotein from the aerobic carbon monoxide utilizing carboxidotrophic eubacterium Hydrogenophaga pseudoflava, have been determined from the enzyme synthesized at high (Mo(plus) CODH) and low intracellular molybdenum content (Mo(minus) CODH) at 2.25 A and 2.35 A resolution, respectively. The structures were solved by Patterson search methods utilizing the enzyme from Oligotropha carboxidovorans as the initial model. The CODHs from both sources are structurally very much conserved and show the same overall fold, architecture and arrangements of the molybdopterin-cytosine dinucleotide-type of molybdenum cofactor, the type I and type II [2Fe-2S] clusters and the flavin-adenine dinucleotide. Unlike the CODH from O. carboxidovorans, the enzyme from H. pseudoflava reveals a unique post-translationally modified C(gamma)-hydroxy-Arg384 residue which precedes the catalytically essential S-selanyl-Cys385 in the active-site loop. In addition, the Trp193 which shields the isoalloxazine ring of the flavin-adenine dinucleotide in the M subunit of the H. pseudoflava CODH is a Tyr193 in the O. carboxidovorans CODH. The hydrogen bonding interaction pattern of the molybdenum cofactor involves 27 hydrogen bonds with the surrounding protein. Of these, eight are with the cytosine moiety, eight with the pyrophosphate, six with the pyranopterin, and five with the ligands of the Mo ion. The structure of the catalytically inactive Mo(minus) CODH indicates that an intracellular Mo-deficiency affects exclusively the active site of the enzyme as an incomplete non-functional molybdenum cofactor was synthesized. The 5'-CDP residue was present in Mo(minus) CODH, whereas the Mo-pyranopterin moiety was absent. In Mo(plus) CODH the selenium faces the Mo ion and flips away from the Mo site in Mo(minus) CODH. The different side-chain conformations of the active-site residues S-selanyl-Cys385 and Glu757 in Mo(plus) and Mo(minus) CODH indicate a side-chain flexibility and a function of the Mo ion in the proper orientation of both residues.
J Mol Biol 2000 Sep 01
PMID:The effect of intracellular molybdenum in Hydrogenophaga pseudoflava on the crystallographic structure of the seleno-molybdo-iron-sulfur flavoenzyme carbon monoxide dehydrogenase. 1096 17

In phosphatidylcholine (PC)-containing prokaryotes, only the methylation pathway of PC biosynthesis was thought to occur. However, a second choline-dependent pathway for PC formation, the PC synthase (Pcs) pathway, exists in Sinorhizobium (Rhizobium) meliloti in which choline is condensed with CDP-diacylglyceride. Here, we characterize the methylation pathway of PC biosynthesis in S. meliloti. A mutant deficient in phospholipid N-methyltransferase (Pmt) was complemented with a S. meliloti gene bank and the complementing DNA was sequenced. A gene coding for a S-adenosylmethionine-dependent N-methyltransferase was identified as the sinorhizobial Pmt, which showed little similarity to the corresponding enzyme from Rhodobacter sphaeroides. Upon expression of the sinorhizobial Pmt, besides phosphatidylcholine, the methylated intermediates of the methylation pathway, monomethylphosphatidylethanolamine and dimethylphosphatidylethanolamine, are also formed. When Pmt-deficient mutants of S. meliloti are grown on minimal medium, they cannot form PC, and they grow significantly more slowly than the wild type. Growth of the Pmt-deficient mutant in the presence of choline allows for PC formation via the Pcs pathway and restores wild-type-like growth. Double knock-out mutants, deficient in Pmt and in Pcs, are unable to form PC and show reduced growth even in the presence of choline. These results suggest that PC is required for normal growth of S. meliloti.
Mol Microbiol 2000 Aug
PMID:Inactivation of the gene for phospholipid N-methyltransferase in Sinorhizobium meliloti: phosphatidylcholine is required for normal growth. 1097 99

Cytidine diphosphate-diacylglycerol (CDP-DAG), an obligatory intermediate compound in the biosynthesis of the major anionic and zwitterionic phospholipids, is synthesized by CDP-DAG synthase (CDS). The gene encoding CDS was isolated from the human malaria parasite Plasmodium falciparum, based on sequence conservation to CDS from other organisms. The P. falciparum gene is located as a single copy on chromosome 14. The open reading frame (ORF) of PfCDS gene encodes a putative protein of 667 amino acids and 78 kDa. Only the C-terminal 422 amino acids share 40% homology with eukaryotic CDSs. The very long and non-conserved N-terminal region of 245 amino acids is hydrophilic and contains asparagine-rich and repetitive sequences. Two mRNA of 3.5 and 4 kb were detected. Transcription is developmentally regulated during the asexual intraerythrocytic cycle, being the weakest in the ring-stage. PfCDS enzyme activities in infected erythrocytes correlates with the transcription pattern, consistent with an increased synthesis of phospholipids in trophozoites and schizonts. Antisera raised against two synthetic peptides from the C-terminal region of PfCDS detected a single protein of 51 kDa in Western blot analysis, specific for parasitized erythrocytes. A protein of 28 kDa was recognized by an antiserum against an N-terminal peptide, indicating that PfCDS is proteolytically processed. Expression of 51- and 28-kDa proteins was developmentally regulated similar to regulation of the transcripts and the enzyme activity. The conserved C-terminal region of PfCDS, cloned into a eukaryote expression vector and transfected in COS-7 cells, showed a two-fold increase CDP-DAG synthase activities, indicating that the isolated gene most likely encoded the P. falciparum CDS enzyme.
Mol Biochem Parasitol 2000 Sep
PMID:Characterization of Plasmodium falciparum CDP-diacylglycerol synthase, a proteolytically cleaved enzyme. 1098 48

The enzyme CMP-Kdo synthetase (CKS) catalyzes the activation of the sugar Kdo (2-keto-3-deoxy-manno-octonic acid) by forming a monophosphate diester. CKS is a pharmaceutical target because CMP-Kdo is used in the biosynthesis of lipopolysaccharides that are vital for Gram-negative bacteria. We have refined the structure of the unligated capsule-specific CKS from Escherichia coli at 1.8 A resolution (1 A=0.1 nm) and we have established the structures of its complexes with the substrate CTP, with CDP and CMP as well as with the product analog CMP-NeuAc (CMP-sialate) by X-ray diffraction analyses at resolutions between 2.1 A and 2.5 A. The N-terminal domains of the dimeric enzyme bind CTP in a peculiar nucleotide-binding fold, whereas the C-terminal domains form the dimer interface. The observed binding geometries together with the amino acid variabilities during evolution and the locations of a putative Mg(2+) and of a very strongly bound water molecule suggest a pathway for the catalysis. The N-terminal domain shows sequence homology with the CMP-NeuAc synthetases. Moreover, the chain fold and the substrate-binding position of CKS resemble those of other enzymes processing nucleotide-sugars.
J Mol Biol 2001 Sep 07
PMID:The structure of CMP:2-keto-3-deoxy-manno-octonic acid synthetase and of its complexes with substrates and substrate analogs. 1154 92

In the past decade, mitochondrial DNA (mtDNA) of 826 representative East Asians and Papuans has been typed by high-resolution (14-enzyme) restriction fragment length polymorphism (RFLP) analysis. Compared with mtDNA control region sequencing, RFLP typing of the complete human mitochondrial DNA generally yields a cleaner phylogeny, the nodes of which can be dated assuming a molecular clock. We present here a novel star contraction algorithm which rigorously identifies starlike nodes (clusters) diagnostic of prehistoric demographic expansions. Applied to the Asian and Papuan data, we date the out-of-Africa migration of the ancestral mtDNA types that founded all Eurasian (including Papuan) lineages at 54,000 years. While the proto-Papuan mtDNA continued expanding at this time along a southern route to Papua New Guinea, the proto-Eurasian mtDNA appears to have drifted genetically and does not show any comparable demographic expansion until 30,000 years ago. By this time, the East Asian, Indian, and European mtDNA pools seem to have separated from each other, as postulated by the weak Garden of Eden model. The east Asian expansion entered America about 25,000 years ago, but was then restricted on both sides of the Pacific to more southerly latitudes during the Last Glacial Maximum around 20,000 years ago, coinciding with a chronological gap in our expansion dates. Repopulation of northern Asian latitudes occurred after the Last Glacial Maximum, obscuring the ancestral Asian gene pool of Amerinds.
Mol Biol Evol 2001 Oct
PMID:Phylogenetic star contraction applied to Asian and Papuan mtDNA evolution. 1155 93

In a screen for temperature-sensitive (37 degrees C) mutants of Saccharomyces cerevisiae that are defective in the proper localization of the Golgi transmembrane protein Emp47p, we uncovered a constitutive loss-of-function mutation in CYS3/STR1, the gene coding for cystathionine-gamma-lyase. We showed by immunofluorescence, sucrose-gradient analysis and quantitative Western analysis that the mutant mislocalized Emp47p to the vacuole at high temperature, while Golgi structures were apparently normal and biosynthetic routing of the vacuolar carboxypeptidase Y (CPY) and the plasma membrane GPI-anchored protein Gas1p were unaffected. The effect of high temperature on Emp47p localization, as well as the temperature sensitivity of the mutant strain on rich medium, appear to be caused by oxidative stress and are correlated with severe reductions in the intracellular levels of low-molecular-weight thiols. In accordance with this conclusion, cys3-2 mutant cells were more sensitive to the oxidizing agent 1-chloro-2,4-dinitrobenzene, which also aggravated the mislocalization of Emp47p observed at high temperature. Furthermore, all the phenotypes of the mutant were completely complemented by exogenous supply of the main low-molecular-weight thiol, glutathione (GSH) and, importantly, the thiol beta-mercaptoethanol reversed the temperature sensitivity of the mutant. A comparison of our mutant with a mutant defective in GSH synthesis showed that gsh1Delta cells were similar to wild-type cells under the stress conditions tested, with the exception of one novel oxidative stress-related phenotype that is observed in both cys3-2 and gsh1Delta mutant cells - a defect in CDP-DAG metabolism upon shift to the non-permissive temperature. As most of the stress-related phenotypes of cys3-2 mutant cells are more severe than those seen in gsh1Delta cells, we conclude that cysteine as such is required and sufficient to confer some degree of protection from oxidative stress in yeast cells.
Mol Genet Genomics 2001 Nov
PMID:Yeast cys3 and gsh1 mutant cells display overlapping but non-identical symptoms of oxidative stress with regard to subcellular protein localization and CDP-DAG metabolism. 1171 78

CDP-diacylglycerol synthase (CDS) is a key rate-limiting enzyme in the phospholipid metabolism of Plasmodium falciparum, converting phosphatidic acid to CDP-diacylglycerol. The CDS gene is predominantly expressed in the mature intraerythrocytic stages. Consequently, we physically and functionally characterized the CDS gene promoter. The mRNA transcription initiation site was mapped 121 bp upstream of the CDS gene translation start site. A 1909 bp 5' upstream sequence was isolated and found to be transcriptionally active thus constituting a functional CDS promoter. Mapping of this promoter identified a 44 bp cis-acting sequence, located between -1640 and -1596 bp upstream of the ATG codon, essential for efficient transcriptional activity. This 44 bp sequence binds specifically to nuclear factors from trophozoite stage parasites. We further showed that a 24 bp element, lying within the 44 bp sequence, mediates the specific binding to nuclear proteins and shows no significant homology to known eukaryotic DNA consensus sequence elements that bind transcription factors. The deletion of the 24 bp element abrogated promoter activity, indicating that this cis-acting sequence element is essential for efficient transcription of the CDS gene.
Mol Biochem Parasitol 2002 Apr 30
PMID:A 24 bp cis-acting element essential for the transcriptional activity of Plasmodium falciparum CDP-diacylglycerol synthase gene promoter. 1198 65


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