Yi Ying-Chen, Shih I-Tai, Yu Tzu-Hsuan, Lee Yen-Ju, Ng I-Son
Department of Chemical Engineering, National Cheng Kung University, Tainan, 70101, Taiwan.
Bioresour Bioprocess. 2021 Oct 13;8(1):100. doi: 10.1186/s40643-021-00455-6.
5-Aminolevulinic acid (5-ALA), a non-proteinogenic five-carbon amino acid, has received intensive attentions in medicine due to its approval by the US Food and Drug Administration (FDA) for cancer diagnosis and treatment as photodynamic therapy. As chemical synthesis of 5-ALA performed low yield, complicated processes, and high cost, biosynthesis of 5-ALA via C4 (also called Shemin pathway) and C5 pathway related to heme biosynthesis in microorganism equipped more advantages. In C4 pathway, 5-ALA is derived from condensation of succinyl-CoA and glycine by 5-aminolevulic acid synthase (ALAS) with pyridoxal phosphate (PLP) as co-factor in one-step biotransformation. The C5 pathway involves three enzymes comprising glutamyl-tRNA synthetase (GltX), glutamyl-tRNA reductase (HemA), and glutamate-1-semialdehyde aminotransferase (HemL) from α-ketoglutarate in TCA cycle to 5-ALA and heme. In this review, we describe the recent results of 5-ALA production from different genes and microorganisms via genetic and metabolic engineering approaches. The regulation of different chassis is fine-tuned by applying synthetic biology and boosts 5-ALA production eventually. The purification process, challenges, and opportunities of 5-ALA for industrial applications are also summarized.
5-氨基乙酰丙酸（5-ALA）是一种非蛋白质ogenic的五碳氨基酸，由于其被美国食品药品监督管理局（FDA）批准用于癌症诊断和作为光动力疗法的治疗，因此在医学领域受到了广泛关注。由于5-ALA的化学合成产率低、过程复杂且成本高，通过与微生物中血红素生物合成相关的C4（也称为舍明途径）和C5途径进行5-ALA的生物合成具有更多优势。在C4途径中，5-ALA由琥珀酰辅酶A和甘氨酸在5-氨基乙酰丙酸合酶（ALAS）的作用下缩合而成，吡哆醛磷酸（PLP）作为辅因子参与一步生物转化。C5途径涉及三种酶，包括谷氨酰胺-tRNA合成酶（GltX）、谷氨酰胺-tRNA还原酶（HemA）和谷氨酸-1-半醛转氨酶（HemL），从三羧酸循环中的α-酮戊二酸生成5-ALA和血红素。在这篇综述中，我们描述了通过遗传和代谢工程方法从不同基因和微生物生产5-ALA的最新结果。通过应用合成生物学对不同底盘进行精细调控，最终提高了5-ALA的产量。还总结了5-ALA在工业应用中的纯化过程、挑战和机遇。
