Abstract
Abstract Since the discovery and sequencing of 6 deoxyerythronolide B synthase twenty years ago, this exceptionally large, multifunctional protein remains the paradigm for the understanding of the structure and biochemical function of modular polyketide synthases.
Highlights
Each homodimeric dEB synthase (DEBS) subunit contains two 160–200-kDa protein modules, each responsible for a single round of polyketide chain extension and functional group modification
The striking colinearity between the organization of the constituent biosynthetic domains encoded by the DEBS genes and the order of the biochemical reactions that generate 6-deoxyerythronolide B (6-dEB) had originally encouraged the hope that the sequence of any newly discovered polyketide synthase (PKS) would allow the ready prediction of the chemical structure of the derived polyketide product
Unlike the unidirectionally transcribed DEBS cluster, a variety of modular PKS genes are either divergently or convergently transcribed such that the sequential order of the open reading frames found in the genome does not correspond to the temporal order in which they exercise their biochemical function (12)
Summary
The biosynthetic intermediates never leave the polyketide synthase (PKS) but are passed along the DEBS assembly line from one acyl carrier protein (ACP) domain to the next. Each homodimeric DEBS subunit contains two 160–200-kDa protein modules, each responsible for a single round of polyketide chain extension and functional group modification. All six DEBS modules contain three core domains consisting of 1) a -ketoacyl-ACP synthase (the ketosynthase (KS) domain) that catalyzes the key polyketide chainbuilding reaction, a decarboxylative condensation of a methylmalonyl-ACP building block with the polyketide chain provided by the upstream PKS module 2 The abbreviations used are: 6-dEB, 6-deoxyerythronolide B; DEBS, 6-dEB synthase; PKS, polyketide synthase; ACP, acyl carrier protein; FAS, fatty acid synthase; KS, -ketoacyl-ACP synthase; AT, acyltransferase; KR, -ketoacyl-ACP reductase; DH, dehydratase; ER, enoyl reductase; NDK-SNAc, natural diketide (2S,3R)-2-methyl-3-hydroxypentanoyl-N-acetylcysteamine thioester. Cyclization of the full-length macrocyclic polyketide and release of 6-dEB are controlled by a dedicated thioesterase domain located at the C terminus of the most downstream module
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