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Query: UNIPROT:P06889 (Mol)
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Sterol 14 alpha-demethylase (CYP51) is the single cytochrome P450 (CYP) required for sterol biosynthesis in different phyla, and it is the most widely distributed P450 gene family being found in all biological kingdoms. It catalyzes the first step following cyclization in sterol biosynthesis such as removal of the 14 alpha-methyl group from lanosterol in the cholesterol biosynthetic pathway, leading to formation of the initial substrate in steroid hormone biosynthesis. CYP51 from different phyla have low sequence similarity across kingdoms and contain only about 40 conserved amino acid residues in the whole family. An attempt to predict the possible role of these conserved residues is being made by a combination of the results of site-directed mutagenesis and information from the known crystal structure of sterol 14 alpha-demethylase from Mycobacterium tuberculosis.
Mol Cell Endocrinol 2004 Feb 27
PMID:CYP51--the omnipotent P450. 1502 90

Vancomycin is the front-line therapy for treating problematic infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and the spread of vancomycin resistance is an acute problem. Vancomycin blocks cross-linking between peptidoglycan intermediates by binding to the D-Ala-D-Ala termini of bacterial cell wall precursors, which are the substrate of transglycosylase/transpeptidase. We have characterized a cluster of seven genes (vanSRJKHAX) in Streptomyces coelicolor that confers inducible, high-level vancomycin resistance. vanHAX are orthologous to genes found in vancomycin-resistant enterococci that encode enzymes predicted to reprogramme peptidoglycan biosynthesis such that cell wall precursors terminate in D-Ala-D-Lac rather than D-Ala-D-Ala. vanR and vanS encode a two-component signal transduction system that mediates transcriptional induction of the seven van genes. vanJ and vanK are novel genes that have no counterpart in previously characterized vancomycin resistance clusters from pathogens. VanK is a member of the Fem family of enzymes that add the cross-bridge amino acids to the stem pentapeptide of cell wall precursors, and vanK is essential for vancomycin resistance. The van genes are organized into four transcription units, vanRS, vanJ, vanK and vanHAX, and these transcripts are induced by vancomycin in a vanR-dependent manner. To develop a sensitive bioassay for inducers of the vancomycin resistance system, the promoter of vanJ was fused to a reporter gene conferring resistance to kanamycin. All the inducers identified were glycopeptide antibiotics, but teicoplanin, a membrane-anchored glycopeptide, failed to act as an inducer. Analysis of mutants defective in the vanRS and cseBC cell envelope signal transduction systems revealed significant cross-talk between the two pathways.
Mol Microbiol 2004 May
PMID:Characterization of an inducible vancomycin resistance system in Streptomyces coelicolor reveals a novel gene (vanK) required for drug resistance. 1513 Jan 28

Staphylococcus aureus peptidoglycan is cross-linked via a characteristic pentaglycine interpeptide bridge. Genetic analysis had identified three peptidyltransferases, FemA, FemB and FemX, to catalyse the formation of the interpeptide bridge, using glycyl t-RNA as Gly donor. To analyse the pentaglycine bridge formation in vitro, we purified the potential substrates for FemA, FemB and FemX, UDP-MurNAc-pentapeptide, lipid I and lipid II and the staphylococcal t-RNA pool, as well as His-tagged Gly-tRNA-synthetase and His-tagged FemA, FemB and FemX. We found that FemX used lipid II exclusively as acceptor for the first Gly residue. Addition of Gly 2,3 and of Gly 4,5 was catalysed by FemA and FemB, respectively, and both enzymes were specific for lipid II-Gly1 and lipid II-Gly3 as acceptors. None of the FemABX enzymes required the presence of one or two of the other Fem proteins for activity; rather, bridge formation was delayed in the in vitro system when all three enzymes were present. The in vitro assembly system described here will enable detailed analysis of late, membrane-associated steps of S. aureus peptidoglycan biosynthesis.
Mol Microbiol 2004 Jul
PMID:In vitro assembly of a complete, pentaglycine interpeptide bridge containing cell wall precursor (lipid II-Gly5) of Staphylococcus aureus. 1522 43

Two quantitative nucleic acid sequence-based amplification assays (QT-NASBA) based on Pfs16 and Pfs25, have been developed to quantify sexual stage commitment and mature gametocytes of Plasmodium falciparum. Pfs16 mRNA is expressed in all sexual forms including sexually committed ring stages while expression of Pfs25 mRNA is restricted to late stage gametocytes. Both assays showed a sensitivity of one sexual stage parasite/microl of blood. Blood samples from experimentally infected non-immune human volunteers were tested for Plasmodium falciparum by standard microscopy, a previously developed asexual 18S rRNA QT-NASBA, Pfs16 and Pfs25 mRNA QT-NASBA. Pfs16 QT-NASBA was positive in 9 out of 10 volunteers within 48 h after first detection of 18S rRNA, mostly before or at the day of positive microscopy. In contrast, the Pfs25 mRNA QT-NASBA was negative during the 28 days of follow-up, but consistently positive in gametocyte samples from naturally infected Kenyan patients. These data suggest that sexual stage commitment can occur early in the blood-stage infection without successful maturation into infectious gametocytes. In conclusion, Pfs16 and Pfs25 QT-NASBA assays in combination with a previously developed asexual stage QT-NASBA allow for the separate quantification of all developmental stages present in the circulation. The application of sexual stage QT-NASBA assays may contribute to a better understanding of the biology and epidemiology of malaria transmission.
Mol Biochem Parasitol 2004 Sep
PMID:Quantification of Plasmodium falciparum gametocytes in differential stages of development by quantitative nucleic acid sequence-based amplification. 1527 49

The approximately 500 species of the cichlid fish species flock of Lake Victoria, East Africa, have evolved in a record-setting 100,000 years and represent one of the largest adaptive radiations. We examined the population structure of the endangered cichlid species Xystichromis phytophagus from Lake Kanyaboli, a satellite lake to Lake Victoria in the Kenyan Yala wetlands. Two sets of molecular markers were analysed--sequences of the mitochondrial control region as well as six microsatellite loci--and revealed surprisingly high levels of genetic variability in this species. Mitochondrial DNA sequences failed to detect population structuring among the three sample populations. A model-based population assignment test based on microsatellite data revealed that the three populations most probably aggregate into a larger panmictic population. However, values of population pairwise FST indicated moderate levels of genetic differentiation for one population. Eleven distinct mitochondrial haplotypes were found among 205 specimens of X. phytophagus, a relatively high number compared to the total number of 54 haplotypes that were recovered from hundreds of specimens of the entire cichlid species flock of Lake Victoria. Most of the X. phytophagus mitochondrial DNA haplotypes were absent from the main Lake Victoria, corroborating the putative importance of satellite lakes as refugia for haplochromine cichlids that went extinct from the main lake in the last decades and possibly during the Late Pleistocene desiccation of Lake Victoria.
Mol Ecol 2004 Sep
PMID:Population-structure and genetic diversity in a haplochromine cichlid fish [corrected] of a satellite lake of Lake Victoria. 1531 73

This study constitutes the first investigation of the phylogeographic structure of a forest bird distributed throughout the montane and lowland forest biomes of Africa. The key objective was to investigate the importance of Pleistocene climatic cycles on avian diversification across Africa. The Olive Sunbird is a relatively large polytypic sunbird widely distributed throughout evergreen, montane and coastal forests in Africa. Recently, it was split into two species, the Eastern Olive Sunbird (Nectarinia olivacea) and the Western Olive Sunbird (Nectarinia obscura), based on morphological grounds. Analyses of a 395bp fragment of the mtDNA NADH subunit 3 gene with flanking tRNA sequences, from 196 individuals of N. olivacea and 86 from N. obscura indicate that genetic divergence levels are low (1.0-2.4%) across some 9000km, from Ghana in the northwest of Africa to KwaZulu-Natal in eastern South Africa. Neither currently recognized Olive Sunbird species were monophyletic using either parsimony or likelihood tree-building methods. Phi(ST) values suggested that there was less variation partitioned among species than between most neighboring regions. Genetic diversity within the N. olivacea/obscura complex was dominated by three star-like phylogenies linked to each other by a single mutational step and two subnetworks (IV and V) separated from the core star-like phylogenies (subnetworks I, II, and III) by five to six mutational steps. The dominant evolutionary mechanism shaping genetic variation within the N. olivacea/obscura complex as identified by nested-clade analyses, appears to be one of range expansion possibly out of East Africa associated with a period of forest expansion during the mid-Pleistocene, some 1.1-0.7 million years ago. Mismatch profiles suggested that secondary contact has occurred between eastern and western lineages within the Ufipa Escarpment and possibly Zimbabwe, as well as between eastern lineages in the Kenyan Highlands and northern Eastern Arc Mts.
Mol Phylogenet Evol 2004 Oct
PMID:Molecular evolution in space and through time: mtDNA phylogeography of the Olive Sunbird (Nectarinia olivacea/obscura) throughout continental Africa. 1532 39

Sterol 14alpha-demethylase (CYP51) is a member of the cytochrome P450 superfamily, widely found in animals, fungi, and plants but present in few prokaryotic groups. CYP51 is currently believed to be the ancestral cytochrome P450 that has been transferred from prokaryotes to eukaryotic kingdoms. We propose an alternate view of CYP51 evolution that has an impact on understanding the evolution of the entire CYP superfamily. Two hundred forty-nine bacterial and four archaeal CYP sequences have been aligned and a bacterial CYP tree designed, showing a separation of two branches. Prokaryotic CYP51s cluster to the minor branch, together with other eukaryote-like CYPs. Mycobacterial and methylococcal CYP51s cluster together (100% bootstrap probability), while Streptomyces CYP51 remains on a distant branch. A CYP51 phylogenetic tree has been constructed from 44 sequences resulting in a ((plant, bacteria),(animal, fungi)) topology (100% bootstrap probability). This is in accordance with the lanosterol/cycloartenol diversification of sterol biosynthesis. The lanosterol branch (nonphotosynthetic lineage) follows the previously proposed topology of animal and fungal orthologues (100% bootstrap probability), while plant and D. discoideum CYP51s belong to the cycloartenol branch (photosynthetic lineage), all in accordance with biochemical data. Bacterial CYP51s cluster within the cycloartenol branch (69% bootstrap probability), which is indicative of a lateral gene transfer of a plant CYP51 to the methylococcal/mycobacterial progenitor, suggesting further that bacterial CYP51s are not the oldest CYP genes. Lateral gene transfer is likely far more important than hitherto thought in the development of the diversified CYP superfamily. Consequently, bacterial CYPs may represent a mixture of genes with prokaryotic and eukaryotic origin.
J Mol Evol 2004 Jul
PMID:New aspects on lanosterol 14alpha-demethylase and cytochrome P450 evolution: lanosterol/cycloartenol diversification and lateral transfer. 1538 7

Sperm are highly specialized cells, and their formation requires the synthesis of a large number of unique mRNAs. However, little is known about the transcriptional mechanisms that direct male germ cell differentiation. Sterol response element binding protein 2gc (SREBP2gc) is a spermatogenic cell-enriched isoform of the ubiquitous transcription factor SREBP2, which in somatic cells is required for homeostatic regulation of cholesterol. SREBP2gc is selectively enriched in spermatocytes and spermatids, and, due to its novel structure, its synthesis is not subject to cholesterol feedback control. This suggested that SREBP2gc has unique cell- and stage-specific functions during spermatogenesis. Here, we demonstrate that this factor activates the promoter for the spermatogenesis-related gene proacrosin in a cell-specific manner. Multiple SREBP2gc response elements were identified within the 5'-flanking and proximal promoter regions of the proacrosin promoter. Mutating these elements greatly diminished in vivo expression of this promoter in spermatogenic cells of transgenic mice. These studies define a totally new function for an SREBP as a transactivator of male germ cell-specific gene expression. We propose that SREBP2gc is part of a cadre of spermatogenic cell-enriched isoforms of ubiquitously expressed transcriptional coregulators that were specifically adapted in concert to direct differentiation of the male germ cell lineage.
Mol Cell Biol 2004 Dec
PMID:Novel role for a sterol response element binding protein in directing spermatogenic cell-specific gene expression. 1557 73

Teas represent a rich source of dietary antioxidants. This paper describes analysis of the antioxidant potential of individual tea phenolics using an on-line high-performance liquid chromatography (HPLC) method. Tea phenolics from Kenyan green and black teas were identified using liquid chromatography--mass spectrometry (LC-MS(n)) in conjunction with the analysis of their 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS+) radical scavenging ability. Antioxidant potential of flavan-3-ols, caffeoylquinic acids, flavonols, and theaflavins was assessed in comparison to the synthetic vitamin E analogue Trolox. (-)-Epigallocatechin gallate was identified as the most potent antioxidant with a Trolox equivalent antioxidant capacity (TEAC) value of 3.0, contributing approximately 30% of the total antioxidant capacity of green tea. Theaflavins retained antioxidant capacity similar to that of (-)-epicatechin monomers whilst conjugated flavonols did not contribute significantly to the antioxidant capacity of either green or black tea. After HPLC analysis of the antioxidant capacity of phenolics in black tea some 80% of antioxidant activity remained unaccounted for indicating the potential importance of thearubigens as antioxidants in black teas.
Mol Nutr Food Res 2005 Jan
PMID:On-line high-performance liquid chromatography analysis of the antioxidant activity of phenolic compounds in green and black tea. 1560 65

Sterol homeostasis in eukaryotic cells relies on the reciprocal interconversion of free sterols and steryl esters. The formation of steryl esters is well characterized, but the mechanisms that control steryl ester mobilization upon cellular demand are less well understood. We have identified a family of three lipases of Saccharomyces cerevisiae that are required for efficient steryl ester mobilization. These lipases, encoded by YLL012/YEH1, YLR020/YEH2, and TGL1, are paralogues of the mammalian acid lipase family, which is composed of the lysosomal acid lipase, the gastric lipase, and four novel as yet uncharacterized human open reading frames. Lipase triple-mutant yeast cells are completely blocked in steryl ester hydrolysis but do not affect the mobilization of triacylglycerols, indicating that the three lipases are required for steryl ester mobilization in vivo. Lipase single mutants mobilize steryl esters to various degrees, indicating partial functional redundancy of the three gene products. Lipase double-mutant cells in which the third lipase is expressed from the inducible GAL1 promoter have greatly reduced steady-state levels of steryl esters, indicating that overexpression of any of the three lipases is sufficient for steryl ester mobilization in vivo. The three yeast enzymes constitute a novel class of membrane-anchored lipases that differ in topology and subcellular localization.
Mol Cell Biol 2005 Mar
PMID:The Saccharomyces cerevisiae YLL012/YEH1, YLR020/YEH2, and TGL1 genes encode a novel family of membrane-anchored lipases that are required for steryl ester hydrolysis. 1571 25


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