BIOSYNTHESIS OF THE ZARAGOZIC ACIDS .1. ZARAGOZIC ACID-A

被引:24
作者
BYRNE, KM
ARISON, BH
NALLINOMSTEAD, M
KAPLAN, L
机构
[1] Merck Research Laboratories, New Jersey 07065-0900, P.O. Box 2000
关键词
D O I
10.1021/jo00057a010
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
The biosynthetic precursors of zaragozic acid A, a member of a new class of squalene synthase inhibitors, were determined. Washed cells of the producing culture, an unidentified sterile fungus, were supplemented with both C-14- and C-13-labeled substrates, and isolated zaragozic acid A was analyzed by scintillation counting and carbon NMR analysis, respectively. Zaragozic acid A is derived from two polyketide chains. Chain A begins with an aromatic ring derived from benzoic acid, itself derived from metabolism of phenylalanine, and continues in a polyketide fashion by condensation of five acetate units. The terminal four carbon atoms of chain A appear to arise from condensation of succinic acid to the polyketide chain, although citric acid cannot be ruled out as a source of the terminal six carbons. The acetyl group at C-4' arises from acetate, and the final two carbons of chain A arise by C-methylation from the methyl Of L-methionine to give the methylene at C-3' and the methyl at C-5'. Chain B is a polyketide formed by condensation of four acetate units and two C-methylations from L-methionine to give the two branched methyl groups at C-4'' and C-6''. Proposals for the biosynthesis of related products zaragozic acids B and C are presented.
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页码:1019 / 1024
页数:6
相关论文
共 18 条
[1]   BIOSYNTHESIS OF NON-ACTIN FROM ACETATE, PROPIONATE, AND SUCCINATE - THE ASSIGNMENT OF ITS C-13 NMR-SPECTRUM BY TWO-DIMENSIONAL CORRELATION SPECTROSCOPY [J].
ASHWORTH, DM ;
ROBINSON, JA ;
TURNER, DL .
JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1982, (09) :491-493
[2]  
BARTIZAL KF, 1991, Patent No. 5026554
[3]  
BARTIZAL KF, 1991, Patent No. 5055487
[4]  
Bartizal KF, 1991, Novel anti-fungal compounds, Patent No. [US5053425 A, 5053425]
[5]   ZARAGOZIC ACIDS - A FAMILY OF FUNGAL METABOLITES THAT ARE PICOMOLAR COMPETITIVE INHIBITORS OF SQUALENE SYNTHASE [J].
BERGSTROM, JD ;
KURTZ, MM ;
REW, DJ ;
AMEND, AM ;
KARKAS, JD ;
BOSTEDOR, RG ;
BANSAL, VS ;
DUFRESNE, C ;
VANMIDDLESWORTH, FL ;
HENSENS, OD ;
LIESCH, JM ;
ZINK, DL ;
WILSON, KE ;
ONISHI, J ;
MILLIGAN, JA ;
BILLS, G ;
KAPLAN, L ;
OMSTEAD, MN ;
JENKINS, RG ;
HUANG, L ;
MEINZ, MS ;
QUINN, L ;
BURG, RW ;
KONG, YL ;
MOCHALES, S ;
MOJENA, M ;
MARTIN, I ;
PELAEZ, F ;
DIEZ, MT ;
ALBERTS, AW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (01) :80-84
[6]  
DARLAND G, UNPUB
[7]   THE SQUALESTATINS, NOVEL INHIBITORS OF SQUALENE SYNTHASE PRODUCED BY A SPECIES OF PHOMA .1. TAXONOMY, FERMENTATION, ISOLATION, PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL-ACTIVITY [J].
DAWSON, MJ ;
FARTHING, JE ;
MARSHALL, PS ;
MIDDLETON, RF ;
ONEILL, MJ ;
SHUTTLEWORTH, A ;
STYLLI, C ;
TAIT, RM ;
TAYLOR, PM ;
WILDMAN, HG ;
BUSS, AD ;
LANGLEY, D ;
HAYES, MV .
JOURNAL OF ANTIBIOTICS, 1992, 45 (05) :639-647
[8]   THE ISOLATION AND STRUCTURE ELUCIDATION OF ZARAGOZIC ACID-C, A NOVEL POTENT SQUALENE SYNTHASE INHIBITOR [J].
DUFRESNE, C ;
WILSON, KE ;
ZINK, D ;
SMITH, J ;
BERGSTROM, JD ;
KURTZ, M ;
REW, D ;
NALLIN, M ;
JENKINS, R ;
BARTIZAL, K ;
TRAINOR, C ;
BILLS, G ;
MEINZ, M ;
HUANG, LY ;
ONISHI, J ;
MILLIGAN, J ;
MOJENA, M ;
PELAEZ, F .
TETRAHEDRON, 1992, 48 (47) :10221-10226
[9]   THE ZARAGOZIC ACIDS - STRUCTURE ELUCIDATION OF A NEW CLASS OF SQUALENE SYNTHASE INHIBITORS [J].
HENSENS, OD ;
DUFRESNE, C ;
LIESCH, JM ;
ZINK, DL ;
REAMER, RA ;
VANMIDDLESWORTH, F .
TETRAHEDRON LETTERS, 1993, 34 (03) :399-402
[10]   THE SQUALESTATINS, NOVEL INHIBITORS OF SQUALENE SYNTHASE PRODUCED BY A SPECIES OF PHOMA .3. BIOSYNTHESIS [J].
JONES, CA ;
SIDEBOTTOM, PJ ;
CANNELL, RJP ;
NOBLE, D ;
RUDD, BAM .
JOURNAL OF ANTIBIOTICS, 1992, 45 (09) :1492-1498