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中国生物工程杂志

China Biotechnology
China Biotechnology  2021, Vol. 41 Issue (1): 103-113    DOI: 10.13523/j.cb.2009004
    
Research Progress in Pyrrologuinoline Quinone Biosynthesis
WANG Guang-lu,WANG Meng-yuan,ZHOU Yi-fei,MA Ke,ZHANG Fan,YANG Xue-peng()
School of Food and Bioengineering, Collaborative Innovation Center of Production and Safety, Zhengzhou University of Light Industry, Zhengzhou 450001, China
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Abstract  

Pyrroloquinoline quinone (PQQ) is a ribosomally synthesized and post-translationally modified peptide that has been recognized as the third class of redox cofactors in addition to the well-known nicotinamides (NAD(P)+) and flavins (FAD, FMN). It is widely distributed in organisms and has physiological functions such as antioxidation. It has broad application prospects in the fields of medicine, food and cosmetics. However, the lack of an efficient microbial cell factory limits the industrial production efficiency of PQQ. In this paper, we reviewed the current research on the biosynthesis pathway of PQQ, the structures of key enzymes, as well as metabolic engineering strategies for the construction of high-yielding strains. These advances will provide a basis for finally achieving stable PQQ biosynthesis in microbial cell factories.



Key wordsPyrroloquinoline quinine      Biosynthesis pathway      Regulation mechanism      Key enzymes     
Received: 03 September 2020      Published: 09 February 2021
ZTFLH:  Q56  
Corresponding Authors: Xue-peng YANG     E-mail: yangxuepeng@zzuli.edu.cn
Cite this article:

WANG Guang-lu, WANG Meng-yuan, ZHOU Yi-fei, MA Ke, ZHANG Fan, YANG Xue-peng. Research Progress in Pyrrologuinoline Quinone Biosynthesis. China Biotechnology, 2021, 41(1): 103-113.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2009004     OR     https://manu60.magtech.com.cn/biotech/Y2021/V41/I1/103

Fig.1 Chemical structure of PQQ
Fig.2 PQQ biosynthesis pathway
Fig.3 The carbon skeleton of PQQ originates from glutamate and tyrosine residues on PqqA
Fig.4 Three-dimensional structure of artificial synthesis PqqA polypeptide
Fig.5 Catalytic effect of PqqD and PqqE on free radical reaction
Fig.6 PqqF/PqqG play the role of peptide hydrolysis in PQQ synthesis
Fig.7 Reaction of Fe2+-dependent PqqB hydroxylation
Fig.8 The catalytic reaction of PqqC: the cyclization of AHQQ and the eight-electron oxidation
Fig.9 A model for the expression of methanol dehydrogenase and PQQ biosynthesis in M. extorquens AM1 (a)Methanol metabolic pathway in M. extorquens AM1 (b)PQQ biosynthesis pathway in M. extorquens AM1 (c)MDH expression regulation model in M. extorquens AM1
菌株 得率(mg/g) 产率[mg/(L·h)] 产量 (mg/L) 参考文献
Bacillus sp. 083114 - - 64.3 [40]
Methylopila sp. YHT-1 9 1.6 113.6 [41]
Methylovorus sp. strain MP68 - 0.9 125.0 [42]
Methylobacillus sp. zju323 105 2.2 162.2 [43]
Methylobacterium extorquens AM1 - - 54.0 [44]
Pseudomonas 0813 - - 425.7 [45]
Hyphomicrobium denitrificans FJNU-6 - 7.6 1 087.0 [46]
K. pneumoniae DSM 2026 - - 0.6 [50]
Gluconobacter oxydans 621H 0. 016 0.011 0.8 [54]
Table 1 Screening strains for synthesis of pyrroloquinoline quinolone by microbial fermentation
[1]   Ouchi A, Nakano M, Nagaoka S, et al. Kinetic study of the antioxidant activity of pyrroloquinolinequinol [PQQH(2), a reduced form of pyrroloquinolinequinone] in micellar solution. Journal of Agricultural and Food Chemistry, 2009,57(2):450-456.
doi: 10.1021/jf802197d pmid: 19108686
[2]   朱欣杰, 程瑶. 吡咯喹啉醌的研究进展. 煤炭与化工, 2011,34(5):20-24.
[2]   Zhu X J, Cheng Y. Research progress of pyrroloquinoline-quinone. Coal and Chemical Industry, 2011,34(5):20-24.
[3]   Rucker R, Storms D, Sheets A, et al. Biochemistry: is pyrroloquinoline quinone a vitamin. Nature, 2005,433(7025):E10-1.
doi: 10.1038/nature03323 pmid: 15689994
[4]   高晓嵘, 丁斐. 抗氧化剂在帕金森病治疗中的研究进展. 南通大学学报(医学版), 2011(3):192-195,199.
[4]   Gao X R, Ding F. Research progress of antioxidants in the treatment of Parkinson’s disease. Journal of Nantong University (Medical Sciences), 2011(3):192-195,199.
[5]   王歆, 汪建华, 刘党生, 等. 吡咯喹啉醌产生菌筛选方法建立及菌种筛选. 微生物学报, 2007(6):982-986.
[5]   Wang X, Wang J H, Liu D S, et al. Establishment of the screening method and isolation of PQQ producing strains. Acta Microbiologica Sinica, 2007(6):982-986.
[6]   Akagawa M, Nakano M, Ikemoto K. Recent progress in studies on the health benefits of pyrroloquinoline quinone. Bioscience Biotechnology and Biochemistry, 2016,80(1):13-22.
[7]   万慧. 氧化葡萄糖酸杆菌中吡咯喹啉醌转运与代谢过程的系统生物学研究. 无锡: 江南大学, 2016.
[7]   Wan H. Systematic biology study on the transport and metabolic process of pyrroloquinoline quinone in Gluconobacter oxidans. Wuxi: Jiangnan University, 2016.
[8]   Ma K, Cui J Z, Ye J B, et al. Pyrroloquinoline quinone from Gluconobacter oxydans fermentation broth enhances superoxide anion-scavenging capacity of Cu/Zn-SOD. Food Chemistry, 2017,230:291-294.
doi: 10.1016/j.foodchem.2017.03.057 pmid: 28407913
[9]   Dunbar K, Tietz J, Cox C L, et al. Identification of an auxiliary leader peptide-binding protein required for azoline formation in ribosomal natural products. Journal of the American Chemical Society, 2015,137(24):7672-7677.
[10]   Shen Y Q, Bonnot F, Imsand E M, et al. Distribution and properties of the genes encoding the biosynthesis of the bacterial cofactor, pyrroloquinoline quinone. Biochemistry, 2012,51(11):2265-2275.
doi: 10.1021/bi201763d pmid: 22324760
[11]   周留柱. 鲍曼不动杆菌生物合成吡咯喹啉醌的研究. 郑州: 郑州轻工业大学, 2019.
[11]   Zhou L Z. The research on pyrroloquinoline quinone biosynthesis in Acinetobacter baumannii. Zhengzhou: Zhengzhou University of Light Industry, 2019.
[12]   Yang X P, Zhong G F, Lin J P, et al. Pyrroloquinoline quinone biosynthesis in Escherichia coli through expression of the Gluconobacter oxydans pqqABCDE gene cluster. Journal of Industrial Microbiology & Biotechnology, 2010,37(6):575-580.
doi: 10.1007/s10295-010-0703-z pmid: 20213113
[13]   Saichana N, Tanizawa K, Pechousek J, et al. PqqE from Methylobacterium extorquens AM1: a radical S-adenosyl-l-methionine enzyme with an unusual tolerance to oxygen. The Journal of Biological Chemistry, 2016,159(1):87-99.
[14]   Latham J, Barr I, Klinman J. At the confluence of ribosomally synthesized peptide modification and radical S-adenosylmethionine (SAM) enzymology. The Journal of Biological Chemistry, 2017,292(40):16397-16405.
[15]   Klinman J, Bonnot F. Intrigues and intricacies of the biosynthetic pathways for the enzymatic quinocofactors: PQQ, TTQ, CTQ, TPQ, and LTQ. Chemical Reviews, 2014,114(8):4343-4365.
pmid: 24350630
[16]   Barr I, Stich T, Gizzi A, et al. X-ray and EPR characterization of the auxiliary Fe-S clusters in the radical SAM enzyme PqqE. Biochemistry, 2018,57(8):1306-1315.
[17]   Saichana N, Tanizawa K, Ueno H, et al. Characterization of auxiliary iron-sulfur clusters in a radical S-adenosylmethionine enzyme PqqE from Methylobacterium extorquens AM1. FEBS Open Bio, 2017,7(12):1864-1879.
doi: 10.1002/2211-5463.12314 pmid: 29226074
[18]   Martins A, Latham J, Martel P, et al. A two-component protease in Methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone. The Journal of Biological Chemistry, 2019,294(41):15025-15036.
[19]   Wei Q E, Ran T T, Ma C C, et al. Crystal structure and function of PqqF protein in the pyrroloquinoline quinone biosynthetic pathway. The Journal of Biological Chemistry, 2016,291(30):15575-15587.
pmid: 27231346
[20]   Koehn E, Latham J, Armand T, et al. Discovery of hydroxylase activity for PqqB provides a missing link in the pyrroloquinoline quinone biosynthetic pathway. Journal of the American Chemical Society, 2019,141(10):4398-4405.
pmid: 30811189
[21]   Latham J, Iavarone A, Barr I, et al. PqqD is a novel peptide chaperone that forms a ternary complex with the radical S-adenosylmethionine protein PqqE in the pyrroloquinoline quinone biosynthetic pathway. The Journal of Biological Chemistry, 2015,290(20):12908-12918.
pmid: 25817994
[22]   Marchler A, Bo Y, Han L Y, et al. CDD/SPARCLE: functional classification of proteins via subfamily domain architectures. Nucleic Acids Research, 2017,45(D1):D200-D203.
[23]   李红月, 曾伟主, 周景文. 高产吡咯喹啉醌扭脱甲基杆菌的高通量选育. 生物工程学报, 2018,34(5):794-802.
[23]   Li H Y, Zeng W Z, Zhou J W. High-throughput screening of Methylobacterium extorquens for high production of pyrroloquinoline quinone. Chinese Journal of Biotechnology, 2018,34(5):794-802.
[24]   Wang G L, Zhou Y F, Ma K, et al. Bioconversion of recombinantly produced precursor peptide pqqA into pyrroloquinoline quinone (PQQ) using a cell-free in vitro system. Protein Expression and Purification, 2021,178:105777.
pmid: 33069826
[25]   Li L, Jiao Z W, Hale L, et al. Disruption of gene pqqA or pqqB reduces plant growth promotion activity and biocontrol of crown gall disease by Rahnella aquatilis HX2. PLoS One, 2014,9(12):e115010.
[26]   Wecksler S, Stoll S, Tran H, et al. Pyrroloquinoline quinone biogenesis: demonstration that PqqE from Klebsiella pneumoniae is a radical S-adenosyl-L-methionine enzyme. Biochemistry, 2009,48(42):10151-10161.
[27]   Wecksler S, Stoll S, Iavarone A, et al. Interaction of PqqE and PqqD in the pyrroloquinoline quinone (PQQ) biosynthetic pathway links PqqD to the radical SAM superfamily. Chemical Communications, 2010,46(37):7031-7033.
[28]   Evans R, Latham J, Xia Y L, et al. Nuclear magnetic resonance structure and binding studies of PqqD, a chaperone required in the biosynthesis of the bacterial dehydrogenase cofactor pyrroloquinoline quinone. Biochemistry, 2017,56(21):2735-2746.
[29]   Tsai T Y, Yang C Y, Shih H L, et al. Xanthomonas campestris PqqD in the pyrroloquinoline quinone biosynthesis operon adopts a novel saddle-like fold that possibly serves as a PQQ carrier. Proteins, 2009,76(4):1042-1048.
[30]   Barr I, Latham J, Iavarone A, et al. Demonstration that the radical s-adenosylmethionine (SAM) enzyme PqqE Catalyzes de novo carbon-carbon cross-linking within a peptide substrate PqqA in the presence of the peptide chaperone PqqD. The Journal of Biological Chemistry, 2016,291(17):8877-8884.
pmid: 26961875
[31]   Lavi A, Ngan C H, Attias D, et al. Detection of peptide-binding sites on protein surfaces: the first step toward the modeling and targeting of peptide-mediated interactions. Proteins, 2013,81(12):2096-2105.
[32]   Vern J K, Walter S, Damodara G. Synthesis of pyrroloquinoline quinone(PQQ): EP20060739658. [2007-12-19].https://www.freepatentsonline.com/EP1866307.html. DOI: US20070072894 A1.
[33]   周怡雯, 陈建华. 新辅酶吡咯喹啉醌研究进展. 中国生化药物杂志, 2008,29(4):279-282.
[33]   Zhou Y W, Chen J H. Progress in the research of pyrroloquinoline quinone. Chinese Journal of Biochemical and Pharmaceutics, 2008,29(4):279-282.
[34]   Podzelinska K, He S M, Wathier M, et al. Structure of PhnP, a phosphodiesterase of the carbon-phosphorus lyase pathway for phosphonate degradation. The Journal of Biological Chemistry, 2009,284(25):17216-17226.
pmid: 19366688
[35]   Ouchi A, Nakano M, Nagaoka S I, et al. Kinetic study of the antioxidant activity of pyrroloquinolinequinol (PQQH(2), a reduced form of pyrroloquinolinequinone) in micellar solution. Journal of Agricultural and Food Chemistry, 2009,57(2):450-456.
[36]   Goodwin P, Anthony C. The biochemistry, physiology and genetics of PQQ and PQQ-containing enzymes. Advances in Microbial Physiology, 1998,40:1-80.
pmid: 9889976
[37]   Ramamoorthi R, Lidstorn M. Transcriptional analysis of pqqD and study of the regulation of pyrroloquinoline quinone biosynthesis in Methylobacterium extorquens AM1. Journal of Bacteriology, 1995,177(1):206-211.
[38]   杨靖, 陈文静, 张敏, 等. 甲基营养菌代谢网络途径和代谢工程改造的研究进展. 生物加工过程, 2017,15(6):9-16.
[38]   Yang J, Chen W J, Zhang M, et al. Advances in metabolic network pathways and metabolic engineering of methylotrophic bacteria. Chinese Journal of Bioprocess Engineering, 2017,15(6):9-16.
[39]   Velterop J, Sellink E, Meulenberg J, et al. Synthesis of pyrroloquinoline quinone in vivo and in vitro and detection of an intermediate in the biosynthetic pathway. Journal of Bacteriology, 1995,177(17):5088-5098.
[40]   徐文, 许然, 张利平. 甲醇利用型吡咯喹啉醌产生菌的筛选及鉴定. 生物技术通报, 2013(1):162-165.
[40]   Xu W, Xu R, Zhang L P. Isolation and identification of PQQ producing strains using methanol-utilizing bacteria. Biotechnology Bulletin, 2013(1):162-165.
[41]   姚红涛, 郑璞. Methylopila sp. YHT-1鉴定及其发酵产吡咯喹啉醌. 食品与生物技术学报, 2016,35(7):778-783.
[41]   Yao H T, Zheng P. Production of pyrroloquinoline quinone by Methylopila sp. YHT-1. Journal of Food Science and Biotechnology, 2016,35(7):778-783.
[42]   Xiong X H, Zhao Y, Ge X, et al. Production and radioprotective effects of pyrroloquinoline quinone. International Journal of Molecular Sciences, 2011,12(12):8913-8923.
[43]   Si Z J, Zhu J Z, Wang W G, et al. Novel and efficient screening of PQQ high-yielding strains and subsequent cultivation optimization. Applied Microbiology and Biotechnology, 2016,100(24):10321-10330.
pmid: 27464830
[44]   李慧芝, 康振, 李江华, 等. 常压室温等离子体诱变扭脱甲基杆菌AM1高产吡咯喹啉醌. 生物工程学报, 2016,32(8):1145-1149.
[44]   Li H Z, Kang Z, Li J H, et al. Mutagenesis of Methylobacterium extorquens AM1 for increasing pyrroloquinoline quinone production by atmospheric and room temperature plasma. Chinese Journal of Biotechnology, 2016,32(8):1145-1149.
[45]   钟杉杉. 吡咯喹啉醌高产菌的筛选、诱变、发酵及基因克隆. 北京: 北京化工大学, 2013.
[45]   Zhong S S. Screening, mutation, fermentation and gene cloning of pyrroloquinoline quinone-producing strain. Beijing: Beijing University of Chemical Technology, 2013.
[46]   柯崇榕. 适应性驯化选育高产吡咯喹啉醌的生丝微菌突变株. 生物工程学报, 2020,36(1):152-161.
[46]   Ke C R. Breeding of Hyphomicrobium denitrificans for high production of pyrroloquinoline quinone by adaptive directed domestication. Chinese Journal of Biotechnolog, 2020,36(1):152-161.
[47]   孙继国, 韩增叶, 葛喜珍, 等. 基于重组大肠杆菌无细胞体系生产吡咯喹啉醌. 生物技术通报, 2014,27(4):164-168.
[47]   Sun J G, Han Z Y, Ge X Z, et al. Exploiting cell-free system of recombinant E. coli to synthesize pyrroloquinoline quinone. Biotechnology Bulletin, 2014,27(4):164-168.
[48]   张军静, 田平芳. 基于全局转录工程促进肺炎克雷伯氏菌吡咯喹啉醌的生物合成. 北京化工大学学报(自然科学版), 2014,41(3):92-96.
[48]   Zhang J J, Tian P F. Enhanced production of pyrroloquinoline quinone in Klebsiella pneumoniae via global transcription machinery engineering. Journal of Beijing University of Chemical Technology (Natural Science Edition), 2014,41(3):92-96.
[49]   王歆, 张惟材. 吡咯喹啉醌生物合成研究进展. 生物技术通讯, 2007,18(3):534-538.
[49]   Wang X, Zhang W C. Advances in biosynthesis of pyrroloquinoline quinone. Letters in Biotechnology, 2007,18(3):534-538.
[50]   孙继国. 利用不同启动子在大肠杆菌与肺炎克雷伯氏菌中合成PQQ的研究. 北京: 北京化工大学, 2013.
[50]   Sun J G. Research on PQQ synthesis in recombinant E.coli and Klebsiella pneumoniae by utilizing different promoters. Beijing: Beijing University of Chemical Technology, 2013.
[51]   Wan H, Xia Y, Li J H, et al. Identification of transporter proteins for PQQ-secretion pathways by transcriptomics and proteomics analysis in Gluconobacter oxydans WSH-003. Frontiers of Chemical Science and Engineering, 2017,11(1):72-88.
[52]   王朝绚. 吡咯喹啉醌工程菌构建及关键基因研究. 北京: 北京化工大学, 2013.
[52]   Wang C X. Engineering strains for production of pyrroloquinoline quinone and dissecting key genes. Beijing: Beijing University of Chemical Technology, 2013.
[53]   鄢芳清, 韩亚昆, 李娟, 等. 大肠杆菌芳香族氨基酸代谢工程研究进展. 生物加工过程, 2017,15(5):32-39,85.
[53]   Yan F Q, Han Y K, Li J, et al. Metabolic engineering of aromatic amino acids in Escherichia coli. Chinese Journal of Bioprocess Engineering, 2017,15(5):32-39,85.
[54]   李盼盼. 氧化葡萄糖酸杆菌合成吡咯喹啉醌的研究. 郑州: 郑州轻工业学院, 2016.
[54]   Li P P. The research on pyrroloquinoline quinone biosynthesis in Gluconobacter oxidans. Zhengzhou: Zhengzhou University of Light Industry, 2016.
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