Arachea Buenafe T, Liu Xuying, Pavlovsky Alexander G, Viola Ronald E
Department of Chemistry, University of Toledo, Toledo, Ohio 43606, USA.
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):205-12. doi: 10.1107/S0907444909052834. Epub 2010 Jan 22.
The enzyme aspartate semialdehyde dehydrogenase (ASADH) catalyzes a critical transformation that produces the first branch-point intermediate in an essential microbial amino-acid biosynthetic pathway. The first structure of an ASADH isolated from a fungal species (Candida albicans) has been determined as a complex with its pyridine nucleotide cofactor. This enzyme is a functional dimer, with a similar overall fold and domain organization to the structurally characterized bacterial ASADHs. However, there are differences in the secondary-structural elements and in cofactor binding that are likely to cause the lower catalytic efficiency of this fungal enzyme. Alterations in the dimer interface, through deletion of a helical subdomain and replacement of amino acids that participate in a hydrogen-bonding network, interrupt the intersubunit-communication channels required to support an alternating-site catalytic mechanism. The detailed functional information derived from this new structure will allow an assessment of ASADH as a possible target for antifungal drug development.
天冬氨酸半醛脱氢酶（ASADH）催化一种关键转化反应，该反应产生了微生物必需氨基酸生物合成途径中的首个分支点中间体。从真菌物种（白色念珠菌）中分离出的ASADH的首个结构已被确定为与其吡啶核苷酸辅因子形成的复合物。这种酶是一种功能性二聚体，其整体折叠和结构域组织与已进行结构表征的细菌ASADH相似。然而，二级结构元件和辅因子结合存在差异，这可能导致这种真菌酶的催化效率较低。通过缺失一个螺旋亚结构域和替换参与氢键网络的氨基酸来改变二聚体界面，会中断支持交替位点催化机制所需的亚基间通信通道。从这个新结构中获得的详细功能信息将有助于评估ASADH作为抗真菌药物开发潜在靶点的可能性。
