Metalloenzyme Mechanisms

我们试图了解生物大分子识别它们的伴侣的机制 形成对人类健康至关重要的功能性大分子组件。分子识别 在大多数(如果不是全部)细胞过程中起着核心作用。失败的识别事件牵涉到 多种疾病状态，从对长短距离信号和细胞的缺陷控制 从核扩散到重要代谢活动的缺陷。这一努力的成功将使这一发现成为可能 新的更好的人类疗法。 一个特定的目标是研究参与人体药物代谢的细胞色素P450(CYP3A4， 正常组织和癌组织中雌激素的生物合成(GYP19)。CYP3A4是主要的 P450在人肝脏中表达，是外源物质清除、代谢的主要途径 大约50%的药物是人类摄取的。细胞色素P450 2 C8在细胞周期中起重要作用 一些治疗药物的代谢，如抗癌药物紫杉醇、抗疟疾药物、抗糖尿病药物和 降胆固醇的他汀类药物。第二个目标是关注人类G蛋白偶联受体 (GPCRs)。GPCRs在用于调节体内平衡的上市药物中占很大比例， 包括视觉、嗅觉、血管张力和神经信号。最初的工作将集中在B2肾上腺素能 一种受体，通过G-蛋白刺激家族的作用激活腺酰环化酶 儿茶酚胺结合。这种受体存在于血管和呼吸道的平滑肌中，作用于血管和呼吸道。 支气管扩张，并与心血管疾病和哮喘有关。系统的调查是 建议重点关注生物系统中的主要识别事件类别：蛋白质-蛋白质 识别，定义影响酶的高阶低聚状态的特异性和亲和力 代谢和受体信号传递；膜识别，了解复合体的作用 影响受体和酶活性的成分混合物(磷脂、脂肪酸、胆固醇)；蛋白质- 小分子识别，确定调节激动剂、拮抗剂和 反向激动剂效应与代谢同质和异质协同作用。

We seek to understand the mechanisms by which biological macromolecules recognize their partners in the formation of functional macromolecular assemblies that are critical to human health. Molecular recognition plays a central role in most, if not all, cellular processes. Failed recognition events have been implicated in numerous disease states, ranging from flawed control of long and short range signaling and cellular proliferation, to defects in important metabolic activities. Success in this endeavor will enable the discovery of new and better human therapeutics. One Specific Aim centers on the cytochrome P450s involved in the human metabolism of drugs (CYP3A4, CYP2C8) and the biosynthesis of estrogens in normal and cancerous tissue (GYP19). CYP3A4 is the major P450 expressed in human liver and represents the main route for xenobiotic clearance, metabolizing approximately 50% of the Pharmaceuticals ingested by man. CYP2C8 plays an important role in the metabolism of a number of therapeutics, such as the anticancer drug taxol, antimalarials, anti-diabetics and the cholesterol lowering statins. A second Aim focuses attention on the human G-protein coupled receptors (GPCRs). GPCRs account for a large fraction of marketed drugs designed to modulate homeostasis, including vision, smell, vascular tone, and neurosignaling. Initial work will focus on the B2adrenergic receptor that activates adenylyl cyclase through action of the stimulatory family of G-proteins upon catecholamine binding. This receptor is found in vascular and airway smooth muscle, functions in vaso- and broncho-dilation and is implicated in cardiovascular disease and asthma. Systematic investigations are proposed that focus on the major classes of recognition events in biological systems: Protein-protein recognition, defining the specificity and affinity of higher order oligomeric states that effect enzymatic metabolism and receptor signaling; Membrane recognition, understanding the role of the complex component mix (phospholipids, fatty acids, cholesterol) effecting receptor and enzyme activities; Protein- small molecule recognition, ascertaining multi-component interactions which regulate agonist, antagonist and reverse agonist effects and metabolic homo- and hetero-tropic cooperativity.