Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Post Polyketide Synthase Carbon-Carbon Bond Formation in Type-II PKS-Derived Natural Products from Streptomyces venezuelae
AU - Robertson, Andrew W
AU - MacLeod, Jeanna M
AU - MacIntyre, Logan W
AU - Forget, Stephanie M
AU - Hall, Steven R
AU - Bennett, Leah G
AU - Correa, Hebelin
AU - Kerr, Russell G
AU - Goralski, Kerry B
AU - Jakeman, David L
PY - 2018/2/16
Y1 - 2018/2/16
N2 - Polyketide synthase (PKS) derived natural products are biosynthesized by head-to-tail addition of acetate and malonate extender units resulting in linear extended-polyketide chains. Despite the well-documented structural diversity associated with PKS-derived natural products, C-C chain branching deviating from the usual linear pattern is relatively rare. Herein, type-II PKS angucyclic natural products containing a hemiaminal functionality were identified and proposed as the parent of a series of C-C-branched analogues. These C-C linked acetate or pyruvate branching units were located at the α-positions on the extended polyketide chains of jadomycins incorporating 3- and 4-aminomethylbenzoic acids. Labeling studies utilizing [1-13C]-d-glucose provided mechanistic evidence that the C-C bond formation occurred as a result of a previously unidentified post-PKS processing, additional to the enzymes encoded within the biosynthetic gene cluster. Selected compounds were evaluated in cytotoxic or antimicrobial assays.
AB - Polyketide synthase (PKS) derived natural products are biosynthesized by head-to-tail addition of acetate and malonate extender units resulting in linear extended-polyketide chains. Despite the well-documented structural diversity associated with PKS-derived natural products, C-C chain branching deviating from the usual linear pattern is relatively rare. Herein, type-II PKS angucyclic natural products containing a hemiaminal functionality were identified and proposed as the parent of a series of C-C-branched analogues. These C-C linked acetate or pyruvate branching units were located at the α-positions on the extended polyketide chains of jadomycins incorporating 3- and 4-aminomethylbenzoic acids. Labeling studies utilizing [1-13C]-d-glucose provided mechanistic evidence that the C-C bond formation occurred as a result of a previously unidentified post-PKS processing, additional to the enzymes encoded within the biosynthetic gene cluster. Selected compounds were evaluated in cytotoxic or antimicrobial assays.
KW - Animals
KW - Antineoplastic Agents/chemistry
KW - Biological Products/chemistry
KW - Carbon/chemistry
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Cell Survival/drug effects
KW - Chlorocebus aethiops
KW - Drug Screening Assays, Antitumor
KW - Fibroblasts/drug effects
KW - Gram-Positive Bacteria/drug effects
KW - Humans
KW - Microbial Sensitivity Tests
KW - Molecular Structure
KW - Polyketide Synthases/chemistry
KW - Streptomyces/metabolism
KW - Vero Cells
U2 - 10.1021/acs.joc.7b02823
DO - 10.1021/acs.joc.7b02823
M3 - Journal article
C2 - 29313335
VL - 83
SP - 1876
EP - 1890
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
SN - 0022-3263
IS - 4
ER -