天然产物中β-位甲基化氨基酸单元的生物合成研究进展

Biosynthetic study of β-methyl amino acid building blocks involved in natural products

相对于组成蛋白质大分子的20种标准氨基酸,更多的非标准氨基酸(将近500种)被引入天然产物的生物合成中,后者对于天然产物发挥独特的生物学功能具有至关重要的作用.β-位甲基化氨基酸作为一类非标准氨基酸,在一些活性天然产物的生物合成中及初级代谢中也有很多报道.它们的生物合成主要通过3种方式:(1)谷氨酸变位酶催化;(2)甲基转移酶和氨基转移酶联合催化;(3)S-腺苷甲硫氨酸自由基酶催化.本文综述了近年来文献中报道的天然产物中β-位甲基氨基酸单元的生物合成方式,通过代谢工程、合成生物学及酶工程的手段,将有助于提高含有该单元的活性天然产物的产量,同时有助于创造更多含有该单元的非天然-天然产物.

Natural products are an important source of pharmaceuticals or drug leads for the human lifes. The biosynthetic studies on these small chemical molecules can offer the possibilities to improve the titers and produce a lot of non-natural natural products with enhanced biological activity. Amino acids are a type of important building blocks of natural products, and apart from twenty proteinogenic amino acids, about five hundred nonproteinogenic amino acids were found to be involved into the biosynthesis of natural products. These nonproteinogenic amino acid units in natural products have been confirmed to play crucial roles in their stabilities and biological activities. β-methyl amino acid is one kind of nonproteinogenic amino acids and has been found in many bioactive secondary metabolites, including daptomycin, streptonigrin, indolemycin and so on, and as well as several primary metabolites such as 3-methyl-glutamate in fermentation process of several Clostridium sp. The β-carbon of amino acids is not an active position for methylation, therefore the methylation at the β-position is still chemically very challenging. Recently, the biosynthetic studies of microbial natural products revealed many novel enzymatic reactions or pathways for amino acid modifications including the β-methylation of amino acids. Up to now, three different biosynthetic pathways for β-methyl amino acids have been reported, including B_（12）-dependent glutamate aminomutase, combination of a methyltransferase and an aminotranferase, and B12-dependent radical SAM methyltransferase. B_（12）-dependent glutamate aminomutase catalyzes the rearrangement of glutamate to generate β-methyl aspartic acid, a building black of Nikkomycins and other natural products. Combination of a methyltransferase and an aminotranferase uses the aminotransferase to generate a-keto acids as the active substrates for the methylation catalzyed by the methyltransferase from amino acids while B12-dependent radical SAM methyltransferase can catalyze the direct methylation at the β-carbon of amino acids via a radical manner. There have been many reviews that summarized the enzymatic modifications of amino acids, but there has been none of literatures covering this type of intereting and useful nonproteinogenic amino acids. This review summarized the recent advances in the biosynthesis of β-methyl amino acids as the building blocks of several natural products and discussed the biosynthetic or enzymatic mechanisms involved in the β-methylation of amino acids in detail. Basesd on the mechanisms of the biosynthesis of these β-methyl amino acids, the application of β-methyl amino acids was proposed in this review. This study may provide new strategies and useful information for improving the yields of the valuable natural products containing β-methyl amino acids and introducing these building blocks into more chemical scaffolds by metabolic engineering, synthetic biology and enzyme engineering methods.