Consequences of binding an S-adenosylmethionine analogue on the structure and dynamics of the thiopurine methyltransferase protein backbone.
Consequences of binding an S-adenosylmethionine analogue on the structure and dynamics of the thiopurine methyltransferase protein backbone.
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结合 S-腺苷甲硫氨酸类似物对硫嘌呤甲基转移酶蛋白主链的结构和动力学的影响。
DOI：
10.1021/bi0492556
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Hodsdon,MichaelE
中科院分区：
文献类型：
--
作者：
Scheuermann,ThomasH;Keeler,Camille;Hodsdon,MichaelE
In humans, the enzyme thiopurine methyltransferase (TPMT) metabolizes 6-thiopurine (6-TP) medications, commonly used for immune suppression and for the treatment of hematopoietic malignancies. Genetic polymorphisms in the TPMT protein sequence accelerate intracellular degradation of the enzyme through an ubiquitylation and proteasomal-dependent pathway. Research has led to the hypothesis that these polymorphisms destabilize the native structure of TPMT, resulting in the formation of misfolded or partially unfolded states, which are subsequently recognized for intracellular degradation. Addition of the cosubstrate,S-adenosylmethionine (SAM), prevents degradation of the TPMT polymorphs in experimental assays, presumably by stabilizing the native structure. Using a bacterial orthologue of TPMT fromPseudomonas syringae, we have used NMR spectroscopy to describe the consequences of binding sinefungin, a SAM analogue, on the structure and dynamics of the TPMT protein backbone. NMR chemical shift mapping experiments localize sinefungin to a highly conserved site in classical methyltransferases. Distal chemical shift changes involving the presumed active site cover implyindirectconformational changes induced by sinefungin, which may play a role in substrate recognition or the catalytic mechanism. Analysis of protein backbone dynamics based on NMR relaxation reveals a combination of complementary effects. Whereas the peripheral, inserted structural elements of the TPMT topology are conformationally stabilized by the presence of sinefungin, a consistent increase in backbone mobility is observed for the central, conserved structural elements. The potential implications for the structural and dynamic effects of binding sinefungin for the catalytic mechanism of the enzyme and the stabilization of the degradation-susceptible TPMT polymorphs are discussed.
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EcoK 甲基转移酶识别 DNA。
影响因子：
5.6
作者：
L. Powell;D. Dryden;D. F. Willcock;R. Pain;N. Murray
通讯作者：
N. Murray
影响因子：
2.9
作者：
L. Žídek;M. Stone;S. Lato;M. Pagel;Z. Miao;A. Ellington;M. Novotny
通讯作者：
L. Žídek;M. Stone;S. Lato;M. Pagel;Z. Miao;A. Ellington;M. Novotny
影响因子：
15
作者：
Canet, D;Barthe, P;Roumestand, C
通讯作者：
Roumestand, C
影响因子：
3.6
作者：
Preuss, CV;Wood, TC;Weinshilboum, RM
通讯作者：
Weinshilboum, RM
DOI：
10.1016/s0167-4781(98)00020-7
发表时间：
1998-04-29
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Cournoyer, B;Watanabe, S;Vivian, A
通讯作者：
Vivian, A