STRUCTURAL ANALYSIS OF NAT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在研究为什么某些芳香胺N-乙酰转移酶(NAT)基因多态会导致蛋白质没有乙酰化。NAT因其催化底物化合物的N-或O-乙酰化作用而广为人知，包括杂环胺。人类个体在编码他们的两个NAT同源物中的任何一个的DNA上存在差异：NAT1和NAT2。某些基因多态性与特定癌症类型的易感性有关，并导致蛋白质的酶活性和细胞丰度降低。重要的是，这种活性降低的Nat1同工酶不是乙酰化的，而是在细胞内迅速泛素化的。泛素-蛋白酶体途径因其通过降解控制蛋白质寿命而广为人知。这一系统在NAT催化中可能存在一般的调节作用，这一发现表明，未乙酰化但未乙酰化的人NA1在细胞中泛素化。我们正在用核磁共振波谱研究仓鼠NAT2。仓鼠NAT2与人类NAT1具有底物特异性和81%的序列同源性，并可通过核磁共振进行结构研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are studying why certain arylamine N-acetyltransferase (NAT) polymorphisms result in proteins that are not acetylated. NATs are well known for their role in catalyzing either N- or O-acetylation of substrate compounds, including heterocyclic amines. Individual humans possess differences in the DNA that encodes either of their two NAT homologues: NAT1 and NAT2. Certain polymorphisms are associated with predisposition towards specific cancer types and result in proteins with reduced enzymatic activity and cellular abundance. Importantly NAT1 isozymes with such reduced activity are not acetylated and are rapidly ubiquitylated in cells. The ubiquitin-proteasome pathway is well renowned for its role in controlling protein lifespans via degradation. A general regulatory role may exist for this system in NAT catalysis as suggested by the finding that non-acetylated but not acetylated human NAT1 is ubiquitylated in cells. We are studying by NMR spectroscopy hamster NAT2. Hamster NAT2 shares substrate specificity and 81% sequence identity with human NAT1 and is amenable to structural studies by NMR.