STRUCTURAL STUDIES OF THE '424' REDUCED FORM OF CYSTATHIONE B-SYNTHASE

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。 胱硫氨酸-β-合成酶(CBS)催化同型半胱氨酸和丝氨酸缩合生成胱硫氨酸，这是硫化途径的最后一步，从蛋氨酸循环中除去硫并将其转化为半胱氨酸和谷胱甘肽。由于同型半胱氨酸在心脏病中的已知作用，以及阿尔茨海默病和帕金森病患者同型半胱氨酸调节改变与疾病状态之间的关系，人们对CBS非常感兴趣。CBS是一种5？磷酸吡哆醛依赖的酶，它含有一个血红素辅因子。然而，人们认为血红素不参与酶的催化周转。相反，血红素辅助因子被认为与CBS活性的变构控制有关。Banerjee小组已经证明了血红素辅助因子对CBS的调节是氧化还原介导的，其中Fe(II)形式的活性明显低于Fe(III)形式。氧化态和还原态的亚铁血红素都与蛋白质中的组氨酸和半胱氨酸残基进行轴向配位。这一观点最近受到了挑战，因为分离出了一种新形式的还原CBS，它是由高pH值降低产生的。

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. Cystathionine beta-synthase (CBS) catalyzes the condensation of homocysteine and serine to form cystathionine, the important final step in the transulfuration pathway, removing sulfur from the methionine cycle and committing it to the production of cysteine and glutathione. There has been much interest in CBS due to homocysteine's known role in heart disease, as well as a confirmed relationship between altered homocysteine regulation and disease status for Alzheimers and Parkinsons patients. CBS is a pyridoxal 5?-phosphate dependent enzyme and it contains a heme cofactor. However, the heme is not believed to be involved in the catalytic turnover of the enzyme. Instead the heme cofactor has been implicated in the allosteric control of the rate of activity of CBS. The Banerjee group has shown the regulation of CBS by the heme cofactor to be redox-mediated, where the Fe(II) form shows remarkably decreased activity compared to the Fe(III) form. The oxidized and reduced forms of the heme are both coordinated axially by a histidine and a cysteine residue from the protein. This view was recently challenged with the isolation of a new form of reduced CBS, made by the high pH reduction.