DOI: 10.1111/j.1432-1033.1997.00074.x. Structural Organization of A Multifunctional Polyketide Synthase Involved in the Biosynthesis of the Macrolide Immunosuppressant FK506

Structural Organization of A Multifunctional Polyketide Synthase Involved in the Biosynthesis of the Macrolide Immunosuppressant FK506

10.1111/j.1432-1033.1997.00074.x

Crossref journal-article

Wiley

European Journal of Biochemistry (311)

Abstract

The immunosuppressant FK506 is a 23‐membered macrocyclic polyketide produced by several Streptomyces species. Sequencing of a 19.5‐kb contiguous segment of DNA from the FK506 gene cluster of Streptomyces sp. MA6548 revealed the presence of a single 19.3‐kb open reading frame designated fkbA. fkbA encodes a component of the FK506 polyketide synthase, a complex enzyme system which catalyzes synthesis of the polyketide portion of FK506. The predicted product of gene fkbA is a 630660‐Da protein (6420 amino acids) that contains 19 independent domains with a high degree of amino acid sequence similarity to the catalytic activities of known fatty acid synthases. The identified domains are arranged into four repeated modules with a linear organization precisely as that of animal fatty acid synthase and type I polyketide synthase. Each module participates in one round of chain extension and subsequent processing and thus FkbA polypeptide catalyzes four of the ten condensation steps required for synthesis of the FK506 macrolactone ring. Disruption of fkbA results in the generation of an FK506 non‐producing mutant demonstrating direct involvement of fkbA in the biosynthesis of FK506.

Bibliography

Motamedi, H., Cai, S., Shafiee, A., & Elliston, K. O. (1997). Structural Organization of A Multifunctional Polyketide Synthase Involved in the Biosynthesis of the Macrolide Immunosuppressant FK506. European Journal of Biochemistry, 244(1), 74â80. Portico.

Authors 4

Haideh Motamedi (first)
Sheng‐Jian Cai (additional)
Ali Shafiee (additional)
Keith O. Elliston (additional)

References 32 Referenced 70

10.7164/antibiotics.40.1256
10.1016/0167-5699(92)90111-J
10.1146/annurev.ge.24.120190.000345
10.1146/annurev.mi.47.100193.004303
10.1038/348176a0
10.1126/science.2024119
10.1016/0378-1119(92)90549-5
10.1073/pnas.92.17.7839
10.1002/j.1460-2075.1989.tb08414.x
10.1016/S0021-9258(18)41772-3 / J. Biol. Chem. / Nucleotide sequence and deduced functions of a set of cotranscribed genes of Streptomyces coelicolor A3(2) including the polyketide synthase for the antibiotic actinorhodin by Fernandez‐Moreno M. A. (1992)
10.1002/j.1460-2075.1989.tb08413.x
{'key': 'e_1_2_3_13_2', 'first-page': '29', 'volume-title': 'Developments in industrial microbiology', 'author': 'Byrne K. M.', 'year': '1993'} / Developments in industrial microbiology by Byrne K. M. (1993)
10.1128/jb.178.17.5243-5248.1996
10.1016/0378-1119(95)00191-8
10.1073/pnas.74.12.5463
10.1093/nar/12.1Part1.387
10.1016/0378-1119(92)90083-2
10.1073/pnas.84.13.4445
10.1096/fasebj.8.15.8001737
10.1111/j.1432-1033.1991.tb16052.x
10.1016/0968-0004(84)90184-1
10.1038/343038a0
10.1111/j.1432-1033.1992.tb16603.x
10.1016/0378-1119(92)90602-L
10.1016/0378-1119(95)00800-4
{'key': 'e_1_2_3_27_2', 'first-page': '19388', 'article-title': 'Molecular cloning and sequencing of the genes for mycocerosic acid synthase, a novel fatty acid elongating multifunctional enzyme, from Mycobacterium tuberculosis var', 'volume': '267', 'author': 'Mathur M.', 'year': '1992', 'journal-title': 'bovis Bacillus Calmette-Guerin, J. Biol. Chem.'} / bovis Bacillus Calmette-Guerin, J. Biol. Chem. / Molecular cloning and sequencing of the genes for mycocerosic acid synthase, a novel fatty acid elongating multifunctional enzyme, from Mycobacterium tuberculosis var by Mathur M. (1992)
10.1007/BF00280426
10.1128/jb.177.13.3673-3679.1995
10.1016/0378-1119(90)90435-T
10.1016/0014-5793(95)01119-Y
10.1111/j.1432-1033.1990.tb19252.x
10.1016/S0021-9258(18)41558-X / J. Biol. Chem. / Construction, expression, and characterization of a mutated animal fatty acid synthase deficient in dehydrase function by Joshi A. K. (1993)

Dates

Type	When
Created	21 years, 1 month ago (July 16, 2004, 10:23 a.m.)
Deposited	1 year, 9 months ago (Nov. 23, 2023, 1:27 a.m.)
Indexed	1 month, 2 weeks ago (July 23, 2025, 8:45 a.m.)
Issued	28 years, 7 months ago (Feb. 1, 1997)
Published	28 years, 7 months ago (Feb. 1, 1997)
Published Online	21 years, 1 month ago (July 16, 2004)
Published Print	28 years, 7 months ago (Feb. 1, 1997)

Funders 0

None

BibTeX

@article{Motamedi_1997, title={Structural Organization of A Multifunctional Polyketide Synthase Involved in the Biosynthesis of the Macrolide Immunosuppressant FK506}, volume={244}, ISSN={1432-1033}, url={http://dx.doi.org/10.1111/j.1432-1033.1997.00074.x}, DOI={10.1111/j.1432-1033.1997.00074.x}, number={1}, journal={European Journal of Biochemistry}, publisher={Wiley}, author={Motamedi, Haideh and Cai, Sheng‐Jian and Shafiee, Ali and Elliston, Keith O.}, year={1997}, month=feb, pages={74–80} }

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