Mechanisms of Iron-Sulfur Dependent Reactions
Mechanisms of Iron-Sulfur Dependent Reactions
批准号:
10406673
负责人:
SQUIRE J. BOOKER
金额:
$37.01万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
未结题
起止时间:
2017-04-01 至 2027-03-31
关键词:
AnabolismAntibiotic ResistanceAntibioticsAntifungal AgentsArchitectureBiologicalBiologyCarbapenemsCarbohydratesCarbonCobalaminDNAEnzymesFree RadicalsHealthHumanHybridsIronLipidsMethylationMethyltransferaseNatural ProductsNitrogenOxygenPathway interactionsPhosphorusPrevalenceProcessProteinsRNAReactionResistanceResortS-AdenosylhomocysteineS-AdenosylmethionineSourceSulfurSystemThiostreptonWorkanti-cancerbasecarbanioncofactorenzyme structuremacromoleculemethyl groupsmall moleculetRNA Methyltransferases
中文摘要
项目摘要/摘要
甲基化反应在生物学中的流行和意义已经得到了很好的证实。甲基是
添加到广泛的生物分子上,包括大量的小分子代谢物和天然
产品,以及各种大分子,如蛋白质、DNA、RNA、碳水化合物和类脂。在辽阔的土地上
大多数甲基化反应中,S-腺苷甲硫氨酸(SAM)是添加的甲基的来源。在……里面
经典的甲基转移酶反应,氧、氮和硫等强亲核试剂攻击SP3-
在极性SN2反应中杂化SAM的甲基,得到S-腺苷同型半胱氨酸作为副产物。
碳原子也可以通过这种机制甲基化,但前提是适当的亲核碳负离子可以
已生成。最近,人们发现SAM可以用来甲基化惰性碳或
通过涉及自由基中间体的途径使磷原子亚磷酸化。这些非规范的SAM-
依赖甲基化存在于抗生素、抗真菌、抗癌等多种生物合成途径中。
和除草天然产物,完全由自由基S中的酶催化-
腺苷蛋氨酸超家族。自由基SAM甲基酶目前包括三类(A类,B类,
和C类)基于结构体系结构、辅因要求和作用机制。A类
酶利用半胱氨酸二聚体催化sp2杂化碳中心的甲基化。B类酶的使用
钴胺辅助因子催化sp2和sp3杂化碳中心的甲基化。C类酶
使用两个同时结合的SAM分子来甲基化sp2杂化的碳中心。在所有情况下,
添加的甲基来自SAM的第二个分子。这项工作将继续努力
了解这些自由基SAM甲基酶是如何工作的,特别关注确定结构的努力
具有结合底物、辅因子和中间体的这些酶。重要的系统包括RNA
参与抗生素耐药性的甲基酶,以及参与生物合成的甲基酶
重要的抗生素,如硫链菌素A、诺西肽和碳青霉烯类,目前最后的抗生素
度假村。
英文摘要
PROJECT SUMMARY/ABSTRACT
The prevalence and significance of methylation reactions in biology is well established. Methyl groups are
appended to a wide array of biological molecules, including numerous small-molecule metabolites and natural
products, and various macromolecules, such as proteins, DNA, RNA, carbohydrates, and lipids. In the vast
majority of methylation reactions, S-adenosylmethionine (SAM) is the source of the appended methyl group. In
classical methyltransferase reactions, strong nucleophiles such as oxygen, nitrogen, and sulfur attack the sp3-
hybridized methyl group of SAM in a polar SN2 reaction, affording S-adenosylhomocysteine as a co-product.
Carbon atoms can also be methylated by this mechanism, but only if a suitably nucleophilic carbanion can be
generated. Relatively recently, it has come to light that SAM can be used to methylate inert carbon or
phosphinate phosphorous atoms via pathways involving radical intermediates. These noncanonical SAM-
dependent methylations are found in numerous biosynthetic pathways for antibiotic, antifungal, anticancer,
and herbicidal natural products, and are catalyzed exclusively by enzymes within the radical S-
adenosylmethionine superfamily. Radical SAM methylases currently consist of three classes (Class A, Class B,
and Class C) based on structural architecture, cofactor requirement, and mechanism of action. Class A
enzymes use a Cys dyad to catalyze methylation of sp2-hybridized carbon centers. Class B enzymes use
cobalamin cofactors to catalyze methylation of both sp2- and sp3-hybridized carbon centers. Class C enzymes
use two simultaneously bound molecules of SAM to methylate sp2-hybridized carbon centers. In all cases, the
appended methyl group derives from a second molecule of SAM. This work will continue our efforts to
understand how these radical SAM methylases work, with a particular focus on efforts to determine structures
of these enzymes with bound substrates, cofactors, and intermediates. Important systems include RNA
methylases that are involved in antibiotic resistance, as well as methylases that are involved in the biosynthesis
of important antibiotics, such as thiostrepton A, nosiheptide, and carbapenems, the antibiotics currently of last
resort.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Enzymatic Fluoroalkylation using Te-Adenosyl-Telluromethionine Analogs and Late-Stage Diversification of Natural Products Exhibiting Antibacterial Behavior
-
批准号:10196336
-
项目类别:
-
资助金额:$18.9万
-
财政年份:2021
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Enzymatic Fluoroalkylation using Te-Adenosyl-Telluromethionine Analogs and Late-Stage Diversification of Natural Products Exhibiting Antibacterial Behavior
-
批准号:10372230
-
项目类别:
-
资助金额:$15.75万
-
财政年份:2021
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanisms of Iron-Sulfur Dependent Reactions
-
批准号:10593972
-
项目类别:
-
资助金额:$37.01万
-
财政年份:2017
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Understanding the Biosynthesis of the 2,4-Dimethylindolic Acid Moiety in the Thiopeptide Antibiotic Nosiheptide
-
批准号:9375024
-
项目类别:
-
资助金额:$18.9万
-
财政年份:2017
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Radical Mechanisms of Iron-Sulfur Proteins
-
批准号:9277146
-
项目类别:
-
资助金额:$29.88万
-
财政年份:2017
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Radical strategies for inhibiting the antibiotic resistance protein, Cfr
-
批准号:8684786
-
项目类别:
-
资助金额:$18.02万
-
财政年份:2014
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanisms of Radical-Dependent Biological Methylation
-
批准号:8321351
-
项目类别:
-
资助金额:$27.17万
-
财政年份:2012
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanisms of Radical-Dependent Biological Methylation
-
批准号:8841377
-
项目类别:
-
资助金额:$23.15万
-
财政年份:2012
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanisms of Radical-Dependent Biological Methylation
-
批准号:8461575
-
项目类别:
-
资助金额:$26.17万
-
财政年份:2012
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanisms of Radical-Dependent Biological Methylation
-
批准号:8649058
-
项目类别:
-
资助金额:$27.06万
-
财政年份:2012
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:7933144
-
项目类别:
-
资助金额:$9.1万
-
财政年份:2009
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:7038359
-
项目类别:
-
资助金额:$22.43万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:6727715
-
项目类别:
-
资助金额:$23.01万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:7415136
-
项目类别:
-
资助金额:$25.22万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:6874504
-
项目类别:
-
资助金额:$22.99万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:7582291
-
项目类别:
-
资助金额:$25.2万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:6472905
-
项目类别:
-
资助金额:$23.05万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:6624188
-
项目类别:
-
资助金额:$23.03万
-
财政年份:2002
-
负责人:SQUIRE J. BOOKER
-
依托单位:
Mechanistic Studies of Lipoic Acid Synthase
-
批准号:7265543
-
项目类别:
-
资助金额:$25.25万
-
财政年份:2001
-
负责人:SQUIRE J. BOOKER
-
依托单位:
ACTIVATION OF LYSINE 2,3-AMINOMUTASE
-
批准号:2770823
-
项目类别:
-
资助金额:$1.74万
-
财政年份:1998
-
负责人:SQUIRE J. BOOKER
-
依托单位:
海外基金