1 Department of Biochemistry and University of Missouri-Columbia , Columbia, Missouri.
2 Department of Chemistry, University of Missouri-Columbia , Columbia, Missouri.
Antioxid Redox Signal. 2019 Feb 1;30(4):650-673. doi: 10.1089/ars.2017.7374. Epub 2017 Nov 13.
Proline catabolism refers to the 4-electron oxidation of proline to glutamate catalyzed by the enzymes proline dehydrogenase (PRODH) and l-glutamate γ-semialdehyde dehydrogenase (GSALDH, or ALDH4A1). These enzymes and the intermediate metabolites of the pathway have been implicated in tumor growth and suppression, metastasis, hyperprolinemia metabolic disorders, schizophrenia susceptibility, life span extension, and pathogen virulence and survival. In some bacteria, PRODH and GSALDH are combined into a bifunctional enzyme known as proline utilization A (PutA). PutAs are not only virulence factors in some pathogenic bacteria but also fascinating systems for studying the coordination of metabolic enzymes via substrate channeling. Recent Advances: The past decade has seen an explosion of structural data for proline catabolic enzymes. This review surveys these structures, emphasizing protein folds, substrate recognition, oligomerization, kinetic mechanisms, and substrate channeling in PutA.
Major unsolved structural targets include eukaryotic PRODH, the complex between monofunctional PRODH and monofunctional GSALDH, and the largest of all PutAs, trifunctional PutA. The structural basis of PutA-membrane association is poorly understood. Fundamental aspects of substrate channeling in PutA remain unknown, such as the identity of the channeled intermediate, how the tunnel system is activated, and the roles of ancillary tunnels.
New approaches are needed to study the molecular and in vivo mechanisms of substrate channeling. With the discovery of the proline cycle driving tumor growth and metastasis, the development of inhibitors of proline metabolic enzymes has emerged as an exciting new direction. Structural biology will be important in these endeavors.
脯氨酸分解代谢是指脯氨酸在脯氨酸脱氢酶（PRODH）和 l-谷氨酸 γ-半醛脱氢酶（GSALDH，或 ALDH4A1）的催化下发生 4 电子氧化，生成谷氨酸。这些酶和途径中的中间代谢物与肿瘤生长和抑制、转移、高脯氨酸血症代谢紊乱、精神分裂症易感性、寿命延长以及病原体毒力和存活有关。在一些细菌中，PRODH 和 GSALDH 结合成一种双功能酶，称为脯氨酸利用 A（PutA）。PutAs 不仅是一些致病菌的毒力因子，也是通过底物通道研究代谢酶协调的迷人系统。 最新进展：过去十年中，脯氨酸分解代谢酶的结构数据呈爆炸式增长。本综述调查了这些结构，强调了 PutA 中的蛋白质折叠、底物识别、寡聚化、动力学机制和底物通道。 关键问题：主要未解决的结构靶标包括真核 PRODH、单功能 PRODH 和单功能 GSALDH 之间的复合物，以及所有 PutAs 中最大的三功能 PutA。PutA 与膜结合的结构基础知之甚少。PutA 中底物通道的基本方面仍然未知，例如通道中间产物的身份、隧道系统如何被激活以及辅助隧道的作用。 未来方向：需要新的方法来研究底物通道的分子和体内机制。随着脯氨酸循环驱动肿瘤生长和转移的发现，脯氨酸代谢酶抑制剂的开发已成为一个令人兴奋的新方向。结构生物学在这些努力中很重要。
