STRUCTURAL ANALYSIS OF NAT

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 我们正在研究为什么某些芳胺N-乙酰转移酶（NAT）多态性导致蛋白质不乙酰化。NAT因其在催化底物化合物（包括杂环胺）的N-或O-乙酰化中的作用而众所周知。人类个体在编码两种NAT同源物（NAT 1和NAT 2）的DNA上存在差异。某些多态性与特定癌症类型的易感性相关，并导致蛋白质的酶活性和细胞丰度降低。重要的是，具有这种降低的活性的NAT 1同工酶不被乙酰化，并且在细胞中被快速泛素化。泛素-蛋白酶体途径以其通过降解控制蛋白质寿命的作用而闻名。一个一般的调节作用可能存在于NAT催化的这一系统中，如发现非乙酰化但不乙酰化的人NAT 1在细胞中被泛素化所表明的。我们正在研究通过核磁共振波谱仓鼠NAT 2。NAT 2与人NAT 1具有底物特异性和81%的序列同一性，并且适合通过NMR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.