7-Carboxy-7-deazaguanine Synthase: A Radical S-Adenosyl-l-methionine Enzyme with Polar Tendencies.
7-Carboxy-7-deazaguanine Synthase: A Radical S-Adenosyl-l-methionine Enzyme with Polar Tendencies.
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DOI：
10.1021/jacs.6b11381
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发表时间：
2017-02-08
影响因子：
15
通讯作者：
Bandarian V
中科院分区：
文献类型：
--
作者：
Bruender NA;Grell TA;Dowling DP;McCarty RM;Drennan CL;Bandarian V
自由基S-腺苷-L-甲硫氨酸（SAM）酶广泛分布并催化多种反应。SAM与位点分化的[4Fe-4S]簇的独特铁原子结合，并被还原性切割以产生5′-脱氧腺苷自由基，其启动周转。7-羧基-7-脱氮鸟嘌呤（CDG）合酶（QueE）催化含7-脱氮嘌呤的天然产物的生物合成中的关键步骤。6-羧基蝶呤（6-CP）是天然底物6-羧基-5，6，7，8-四氢蝶呤（CPH4）的氧化类似物，是CDG合酶的替代底物。在促进SAM还原裂解的还原条件下，6-CP转化为6-脱氧腺苷蝶呤（6-dAP），可能是通过5′-脱氧腺苷的自由基加成，然后氧化脱羧形成产物。而在没有强还原剂连二亚硫酸盐存在下，6-CP的羧酸酯被酯化生成6-羧基蝶呤-5 ′-脱氧腺苷酯（6-CP-dAdo酯）。6-CP和SAM的结构研究也揭示了与晶体中形成的酯产物一致的电子密度。6-CP在还原和非还原条件下的差异反应性突出了自由基SAM酶在同一活性位点进行极性和自由基转化的能力。
Radical S-adenosyl-l-methionine (SAM) enzymes are widely distributed and catalyze diverse reactions. SAM binds to the unique iron atom of a site-differentiated [4Fe-4S] cluster and is reductively cleaved to generate a 5′-deoxyadenosyl radical, which initiates turnover. 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes a key step in the biosynthesis of 7-deazapurine containing natural products. 6-Carboxypterin (6-CP), an oxidized analogue of the natural substrate 6-carboxy-5,6,7,8-tetrahydropterin (CPH4), is shown to be an alternate substrate for CDG synthase. Under reducing conditions that would promote the reductive cleavage of SAM, 6-CP is turned over to 6-deoxyadenosylpterin (6-dAP), presumably by radical addition of the 5′-deoxyadenosine followed by oxidative decarboxylation to the product. By contrast, in the absence of the strong reductant, dithionite, the carboxylate of 6-CP is esterified to generate 6-carboxypterin-5′-deoxyadenosyl ester (6-CP-dAdo ester). Structural studies with 6-CP and SAM also reveal electron density consistent with the ester product being formed in crystallo. The differential reactivity of 6-CP under reducing and nonreducing conditions highlights the ability of radical SAM enzymes to carry out both polar and radical transformations in the same active site.