Hydroxymalonyl-acyl carrier protein (ACP) and aminomalonyl-ACP are two additional type I polyketide synthase extender units

被引:106
作者
Chan, Yolande A.
Boyne, Michael T., II
Podevels, Angela M.
Klimowicz, Amy K.
Handelsman, Jo
Kelleher, Neil L.
Thomas, Michael G. [1 ]
机构
[1] Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 USA
[2] Univ Wisconsin, Dept Plant Pathol, Madison, WI 53706 USA
[3] Univ Wisconsin, Microbiol Doctoral Training Program, Madison, WI 53706 USA
[4] Univ Illinois, Dept Chem, Urbana, IL 61801 USA
关键词
antibiotics; combinatorial biosynthesis; CHAIN EXTENSION UNIT; GENE-CLUSTER; PHOSPHOSERINE PHOSPHATASE; ENGINEERED BIOSYNTHESIS; SUBSTRATE-SPECIFICITY; PEPTIDE SYNTHETASES; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; IDENTIFICATION; GELDANAMYCIN;
D O I
10.1073/pnas.0603748103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Combinatorial biosynthesis of type I polyketide synthases is a promising approach for the generation of new structural derivatives of polyketide-containing natural products. A target of this approach has been to change the extender units incorporated into a polyketide backbone to alter the structure and activity of the natural product. One limitation to these efforts is that only four extender units were known: malonyl-CoA, methylmalonyl-CoA, ethylmalonyl-CoA, and methoxymalonyl-acyl carrier protein (ACP). The chemical attributes of these extender units are quite similar, with the exception of the potential hydrogen bonding interactions by the oxygen of the methoxy moiety. Furthermore, the incorporated extender units are not easily modified by using simple chemical approaches when combinatorial biosynthesis is coupled to semisynthetic chemistry. We recently proposed the existence of two additional extender units, hydroxymalonyl-ACP and aminomalonyl-ACP, involved in the biosynthesis of zwittermicin A. These extender units offer unique possibilities for combinatorial biosynthesis and semisynthetic chemistry because of the introduction of free hydroxyl and amino moieties into a polyketide structure. Here, we present the biochemical and mass spectral evidence for the formation of these extender units. This evidence shows the formation of ACP-linked extender units for polyketide synthesis. Interestingly, aminomalonyl-ACP formation involves enzymology typically found in nonribosomal peptide synthesis.
引用
收藏
页码:14349 / 14354
页数:6
相关论文
共 28 条
[1]   Identification of a set of genes involved in the formation of the substrate for the incorporation of the unusual "glycolate" chain extension unit in ansamitocin biosynthesis [J].
Carroll, BJ ;
Moss, SJ ;
Bai, LQ ;
Kato, Y ;
Toelzer, S ;
Yu, TW ;
Floss, HG .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (16) :4176-4177
[2]   BeF3- acts as a phosphate analog in proteins phosphorylated on aspartate:: Structure of a BeF3- complex with phosphoserine phosphatase [J].
Cho, H ;
Wang, WR ;
Kim, R ;
Yokota, H ;
Damo, S ;
Kim, SH ;
Wemmer, D ;
Kustu, S ;
Yan, DL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (15) :8525-8530
[3]   Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase I. Taxonomy, isolation and characterization [J].
Ciciliato, I ;
Corti, E ;
Sarubbia, E ;
Stefanelli, S ;
Gastaldo, L ;
Montanini, N ;
Kurz, M ;
Losi, D ;
Marinelli, F ;
Selva, E .
JOURNAL OF ANTIBIOTICS, 2004, 57 (03) :210-217
[4]   A new class of phosphotransferases phosphorylated on an aspartate residue in an amino-terminal DXDX(T/V) motif [J].
Collet, JF ;
Stroobant, V ;
Pirard, M ;
Delpierre, G ;
Van Schaftingen, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (23) :14107-14112
[5]   The bifunctional glyceryl transferase/phosphatase OzmB belonging to the HAD superfamily that diverts 1,3-bisphosphoglycerate into polyketide biosynthesis [J].
Dorrestein, Pieter C. ;
Van Lanen, Steven G. ;
Li, Wenli ;
Zhao, Chunhua ;
Deng, Zixin ;
Shen, Ben ;
Kelleher, Neil L. .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (32) :10386-10387
[6]   Genetics of Zwittermicin A production by Bacillus cereus [J].
Emmert, EAB ;
Klimowicz, AK ;
Thomas, MG ;
Handelsman, J .
APPLIED AND ENVIRONMENTAL MICROBIOLOGY, 2004, 70 (01) :104-113
[7]   DIVERGENT SEQUENCE MOTIFS CORRELATED WITH THE SUBSTRATE-SPECIFICITY OF (METHYL)MALONYL-COA-ACYL CARRIER PROTEIN TRANSACYLASE DOMAINS IN MODULAR POLYKETIDE SYNTHESES [J].
HAYDOCK, SF ;
APARICIO, JF ;
MOLNAR, I ;
SCHWECKE, T ;
KHAW, LE ;
KONIG, A ;
MARSDEN, AFA ;
GALLOWAY, IS ;
STAUNTON, J ;
LEADLAY, PF .
FEBS LETTERS, 1995, 374 (02) :246-248
[8]   Automated reduction and interpretation of high resolution electrospray mass spectra of large molecules [J].
Horn, DM ;
Zubarev, RA ;
McLafferty, FW .
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY, 2000, 11 (04) :320-332
[9]   Functional expression of genes involved in the biosynthesis of the novel polyketide chain extension unit, methoxymalonyl-acyl carrier protein, and engineered biosynthesis of 2-desmethyl-2-methoxy-6-deoxyerythronolide B [J].
Kato, Y ;
Bai, LQ ;
Xue, Q ;
Revill, WP ;
Yu, TW ;
Floss, HG .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (19) :5268-5269
[10]   Characterization of the biosynthetic gene cluster for the antifungal polyketide soraphen A from Sorangium cellulosum So ce26 [J].
Ligon, J ;
Hill, S ;
Beck, J ;
Zirkle, R ;
Molnár, I ;
Zawodny, J ;
Money, S ;
Schupp, T .
GENE, 2002, 285 (1-2) :257-267