Adhikari Anup, Shakya Sajan, Shrestha Shreesti, Aryal Dipa, Timalsina Kavi Prasad, Dhakal Dipesh, Khatri Yogan, Parajuli Niranjan
Central Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal.
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.
Biotechnol Bioeng. 2023 Dec;120(12):3465-3492. doi: 10.1002/bit.28548. Epub 2023 Sep 10.
Cytochrome P450s belong to a family of heme-binding monooxygenases, which catalyze regio- and stereospecific functionalisation of C-H, C-C, and C-N bonds, including heteroatom oxidation, oxidative C-C bond cleavages, and nitrene transfer. P450s are considered useful biocatalysts for the production of pharmaceutical products, fine chemicals, and bioremediating agents. Despite having tremendous biotechnological potential, being heme-monooxygenases, P450s require either autologous or heterologous redox partner(s) to perform chemical transformations. Randomly distributed P450s throughout a bacterial genome and devoid of particular redox partners in natural products biosynthetic gene clusters (BGCs) showed an extra challenge to reveal their pharmaceutical potential. However, continuous efforts have been made to understand their involvement in antibiotic biosynthesis and their modification, and this review focused on such BGCs. Here, particularly, we have discussed the role of P450s involved in the production of macrolides and aminocoumarin antibiotics, nonribosomal peptide (NRPSs) antibiotics, ribosomally synthesized and post-translationally modified peptide (RiPPs) antibiotics, and others. Several reactions catalyzed by P450s, as well as the role of their redox partners involved in the BGCs of various antibiotics and their derivatives, have been primarily addressed in this review, which would be useful in further exploration of P450s for the biosynthesis of new therapeutics.
细胞色素P450属于血红素结合单加氧酶家族，可催化C-H、C-C和C-N键的区域和立体特异性官能化，包括杂原子氧化、氧化C-C键裂解和氮烯转移。P450被认为是生产药品、精细化学品和生物修复剂的有用生物催化剂。尽管具有巨大的生物技术潜力，但作为血红素单加氧酶，P450需要自体或异源氧化还原伙伴来进行化学转化。在细菌基因组中随机分布的P450以及天然产物生物合成基因簇（BGC）中缺乏特定的氧化还原伙伴，这给揭示它们的药用潜力带来了额外的挑战。然而，人们一直在不断努力了解它们在抗生素生物合成及其修饰中的作用，本综述重点关注此类BGC。在此，我们特别讨论了P450在大环内酯类和氨基香豆素类抗生素、非核糖体肽（NRPS）抗生素、核糖体合成及翻译后修饰肽（RiPPs）抗生素等生产中的作用。本综述主要探讨了P450催化的几种反应，以及它们的氧化还原伙伴在各种抗生素及其衍生物的BGC中的作用，这将有助于进一步探索P450在新治疗药物生物合成中的应用。
