Enzyme ‘Wrench’ Could Be Key to Stronger, More Effective Antibiotics

Builders and factory workers know that getting a job done right requires precision and specialized tools. The same is true when you’re building antibiotic compounds at the molecular level. New findings from North Carolina State University may turn an enzyme that acts as a specialized “wrench” in antibiotic assembly into a set of wrenches that will allow for greater customization. By modifying this enzyme, scientists hope to be able to design and synthesize stronger, more adaptable antibiotics from less expensive, natural compounds.

黄色霉素是一种常见的蚂蚁ibiotic that can be created through natural synthesis; that is, it doesn’t have to be made in a chemistry lab. Nature creates compounds like kirromycin through a factory-like assembly line of enzymes where each performs a specific function, snapping different fragments of molecules together like a jigsaw puzzle. Understanding this process on the molecular level could give chemists the ability to piggyback on nature, synthesizing new antibiotics and cancer drugs with less waste and expense.

NC State chemist Gavin Williams looked at one enzyme in the kirromycin assembly line – KirCII – which is responsible for installing a molecular fragment of kirromycin at one key location. “KirCII is a linchpin enzyme in the assembly,” Williams says. “Natural compounds like kirromycin get built in pieces, with small modules, or blocks of enzymes, linking up sections of the compound in a certain order. Enzymes like KirCII are the wrenches that install the molecular pieces – without them, the molecule doesn’t finish assembling properly.”

Williams and his team performed a molecular analysis of KirCII to determine why and how it latches onto a specific protein within the kirromycin assembly line. They saw that the enzyme has electrical charges on its surface that are complementary to opposite charges on the surface of the protein it binds with. When KirCII finds that protein, the charges match up and it snaps into place.

“We were able to see which areas on KirCII had charges that worked with the target protein,” Williams says. “Hopefully we will be able to use this information to introduce complementary charges onto the surface of other proteins we want KirCII to bind with.

“现在kircii只是一个扳手。通过修改它以适应其他蛋白质，我们可以将其转化为一组不同的扳手并创造完全不同的抗生素。Kirromycin现在不是很有用，但通过使用Kircii来安装来自其他抗生素的碎片，我们将能够混合和匹配并创造新的更强的抗生素。“

Williams’ research appears in the April 10Chemistry and Biology. NC State Ph.D. student Zhixia Ye contributed to the work, as did Ewa Musiol and Tilmann Weber from the Eberhard Karls University of Tübingen, Germany. The research was funded by the National Institutes of Health and the National Science Foundation.

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Note to editors: An abstract of the paper follows.

“Reprogramming Acyl Carrier Protein Interactions of an Acyl-CoA Promiscuoustrans- 乙酰转移酶“

Authors:Zhixia Ye, Gavin J. Williams, Department of Chemistry, North Carolina State University; Ewa M.Musiol, Tilmann Weber, Interfaculty Institute of Microbiology and Infection Medicine, Eberhard Karls University of Tübingen, Germany and the German Center for Infection Research, Tübingen, Germany.
Published:2014年4月10日Chemistry and Biology

Abstract:
酰基载体蛋白（ACP）和蛋白质相互作用trans- 加工酰基转移酶结构域（Trans-ATS）对于许多聚酮合成酶来安装酰基转移酶结构域（Trans-ATS）对于这些相互作用的特异性而言，特别是对于具有异常增量单位特异性的转基因而言，但尚不少。目前，最佳研究的反式非醛基特异性是来自Kirromycin生物合成的kircii。在这里，我们根据利用Kircii的扩展单元滥交，开发了探测ACP相互作用的测定。该测定允许我们识别ACP表面上的残留物，这些残留物有助于Kircii的特定识别。证明，该信息足以将来自不同的生物合成系统的非认知ACP修饰为kircii的基材。该研究结果形成了进一步了解反式：ACP蛋白相互作用和工程模块化聚酮合成酶的基础，以产生类似物。