期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 140, 期 30, 页码 9458-9465出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b03304
关键词
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资金
- NIH [U01CA221230-01, 5T32GM008550]
- Delaware COBRE program from the National Institute of General Medical Sciences [NIGMS P20GM104316-01A1]
- National Institute of General Medical Sciences-NIGMS from the National Institutes of Health [5 P30 GM110758-02, P20GM104316-01A1, P20 GM103446]
- NATIONAL CANCER INSTITUTE [U01CA221230] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM133395, P20GM104316, P30GM110758, T32GM008550, P20GM103446] Funding Source: NIH RePORTER
Uridine diphosphate N-acetyl muramic acid (UDP NAM) is a critical intermediate in bacterial peptidoglycan (PG) biosynthesis. As the primary source of muramic acid that shapes the PG backbone, modifications installed at the UDP NAM intermediate can be used to selectively tag and manipulate this polymer via metabolic incorporation. However, synthetic and purification strategies to access large quantities of these PG building blocks, as well as their derivatives, are challenging. A robust chemoenzymatic synthesis was developed using an expanded NAM library to produce a variety of 2-N-functionalized UDP NAMs. In addition, a synthetic strategy to access bio-orthogonal 3-lactic acid NAM derivatives was developed. The chemoenzymatic UDP synthesis revealed that the bacterial cell wall recycling enzymes MurNAc/GlcNAc anomeric kinase (AmgK) and NAM alpha-1 phosphate uridylyl transferase (MurU) were permissive to permutations at the two and three positions of the sugar donor. We further explored the utility of these derivatives in the fluorescent labeling of both Gram (-) and Gram (+) PG in whole cells using a variety of bio-orthogonal chemistries including the tetrazine ligation. This report allows for rapid and scalable access to a variety of functionalized NAMs and UDP NAMs, which now can be used in tandem with other complementary bio-orthogonal labeling strategies to address fundamental questions surrounding PG's role in immunology and microbiology.
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