A Homologue of the Mycobacterium tuberculosis PapA5 Protein, Rif‐Orf20, Is an Acetyltransferase Involved in the Biosynthesis of Antitubercular Drug Rifamycin B by Amycolatopsis mediterranei S699

Published on May 6, 2005in ChemBioChem2.576
· DOI :10.1002/CBIC.200400387
Yeping Xiong1
Estimated H-index: 1
(OSU: Oregon State University),
Xiumei Wu8
Estimated H-index: 8
(OSU: Oregon State University),
Taifo Mahmud30
Estimated H-index: 30
(OSU: Oregon State University)
Sources
Abstract
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431 Citations
280 Citations
20050.94Microbiology
5 Authors (Jun Xu, ..., Taifo Mahmud)
62 Citations
References12
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#1J.A. Buglino (Kettering University)H-Index: 9
#1John A. Buglino (Kettering University)H-Index: 9
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Abstract Polyketide-associated protein A5 (PapA5) is an acyltransferase that is involved in production of phthiocerol and phthiodiolone dimycocerosate esters, a class of virulence-enhancing lipids produced by Mycobacterium tuberculosis. Structural analysis of PapA5 at 2.75-A resolution reveals a two-domain structure that shares unexpected similarity to structures of chloramphenicol acetyltransferase, dihydrolipoyl transacetylase, carnitine acetyltransferase, and VibH, a non-ribosomal peptide syn...
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Mycobacterium tuberculosis (Mt) produces complex virulence-enhancing lipids with scaffolds consisting of phthiocerol and phthiodiolone dimycocerosate esters (PDIMs). Sequence analysis suggested that PapA5, a so-called polyketide-associated protein (Pap) encoded in the PDIM synthesis gene cluster, as well as PapA5 homologs found in Mt and other species, are a subfamily of acyltransferases. Studies with recombinant protein confirmed that PapA5 is an acetyltransferase. Deletion analysis in Mt demon...
133 CitationsSource
#1Jun Xu (UW: University of Washington)H-Index: 5
#2Taifo Mahmud (UW: University of Washington)H-Index: 30
Last. Heinz G. Floss (UW: University of Washington)H-Index: 51
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Abstract The gene rif orf14 in the rifamycin biosynthetic gene cluster of Amycolatopsis mediterranei S699, producer of the antitubercular drug rifamycin B, encodes a protein of 272 amino acids identified as an AdoMet: 27- O -demethylrifamycin SV methyltransferase. Frameshift inactivation of rif orf14 generated a mutant of A. mediterranei S699 that produces no rifamycin B, but accumulates 27- O -demethylrifamycin SV (DMRSV) as the major new metabolite, together with a small quantity of 27- O -dem...
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#1Elizabeth A. Campbell (Rockefeller University)H-Index: 36
#2Nataliya Korzheva (PHRI: Public Health Research Institute)H-Index: 6
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Abstract Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We determined the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 A away from the active site. The structure, combined with biochemical result...
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The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component analysis is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms ...
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#1Chun-Gyu Kim (UW: University of Washington)H-Index: 4
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Abstract The biosynthesis of ansamycin antibiotics, like rifamycin B, involves formation of 3-amino-5-hydroxybenzoic acid (AHBA) by a novel variant of the shikimate pathway. AHBA then serves as the starter unit for the assembly of a polyketide which eventually links back to the amino group of AHBA to form the macrolactam ring. The terminal enzyme of AHBA formation, which catalyzes the aromatization of 5-deoxy-5-amino-3-dehydroshikimic acid, has been purified to homogeneity from Amycolatopsis med...
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The 54-kbp Type I polyketide synthase gene cluster, most probably involved in rifamycin biosynthesis by Amycolatopsis mediterranei, was cloned in E. coli and completely sequenced. The DNA encodes five closely packed, very large open reading frames reading in one direction. As expected from the chemical structure of rifamycins, ten polyketide synthase modules and a CoA ligase domain were identified in the five open reading frames which contain one to three polyketide synthase modules each. The or...
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#1Paul R. August (UW: University of Washington)H-Index: 1
#1Paul August (UW: University of Washington)H-Index: 16
Last. Heinz G. Floss (UW: University of Washington)H-Index: 51
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Background: The ansamycin class of antibiotics are produced by various Actinomycetes. Their carbon framework arises from the polyketide pathway via a polyketide synthase (PKS) that uses an unusual starter unit. Rifamycin (rif), produced by Amycolatopsis mediterranei , is the archetype ansamycin and it is medically important. Although its basic precursors (3-amino-5-hydroxy benzoic acid AHBA, and acetic and propionic acids) had been established, and several biosynthetic intermediates had been ide...
280 CitationsSource
3-Amino-5-hydroxybenzoic acid was investigated for its ability to induce rifamycin biosynthesis in an appropriate mutant of Nocardia mediterranei and identified as a direct precursor of the seven-carbon amino starter-unit for the biosynthesis of ansamycins. A model for the biosynthesis of different types of ansamycins is presented and discussed.
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Abstract A method has been devised for the electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets. The method results in quantitative transfer of ribosomal proteins from gels containing urea. For sodium dodecyl sulfate gels, the original band pattern was obtained with no loss of resolution, but the transfer was not quantitative. The method allows detection of proteins by autoradiography and is simpler than conventional procedures. The immobilized proteins were det...
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Rifamycin-derived drugs, including rifampin, rifabutin, rifapentine, and rifaximin, have long been used as first-line therapies for the treatment of tuberculosis and other deadly infections. However, the late steps leading to the biosynthesis of the industrially important rifamycin SV and B remain largely unknown. Here, we characterize a network of reactions underlying the biosynthesis of rifamycin SV, S, L, O, and B. The two-subunit transketolase Rif15 and the cytochrome P450 enzyme Rif16 are f...
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Brasilinolides exhibiting potent immunosuppressive and antifungal activities with remarkably low toxicity are structurally characterized by an unusual modified 2-deoxy-L-fucose (2dF) attached to a type I polyketide (PK-I) macrolactone. From the pathogenic producer Nocardia terpenica (Nocardia brasiliensis IFM-0406), a 210 kb genomic fragment was identified by target-specific degenerate primers and subsequently sequenced, revealing a giant nbr gene cluster harboring genes (nbrCDEF) required for T...
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Streptomyces leeuwenhoekii, isolated from the hyperarid Atacama Desert, produces the new ansamycin-like compounds chaxamycins A to D, which possess potent antibacterial activity and moderate antiproliferative activity. We report the development of genetic tools to manipulate S. leeuwenhoekii and the identification and partial characterization of the 80.2-kb chaxamycin biosynthesis gene cluster, which was achieved by both mutational analysis in the natural producer and heterologous expression in ...
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SUMMARY Long-chain-length hydrophobic acyl residues play a vital role in a multitude of essential biological structures and processes. They build the inner hydrophobic layers of biological membranes, are converted to intracellular storage compounds, and are used to modify protein properties or function as membrane anchors, to name only a few functions. Acyl thioesters are transferred by acyltransferases or transacylases to a variety of different substrates or are polymerized to lipophilic storag...
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Covering: 2002 to September 2009 In recent years, a number of gene clusters involved in the biosynthesis of polyketide compounds have been characterized and the genes have been used for designing and developing novel chemical entities by combinatorial biosynthesis. This review covers the highlights of combinatorial biosynthesis using polyketide-modifying enzymes such as oxidoreductases, group transferases, halogenases, cyclases and deoxysugar biosynthesis enzymes, focusing on those from actinomy...
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