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NADPH Metabolism: a Survey of Its Theoretical Characteristics and Manipulation Strategies in Amino Acid Biosynthesis

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NADPH Metabolism: a Survey of Its Theoretical Characteristics and Manipulation Strategies in Amino Acid Biosynthesis Critical Reviews in Biotechnology ISSN: 0738-8551 (Print) 1549-7801 (Online) Journal homepage: http://www.tandfonline.com/loi/ibty20 NADPH metabolism: a survey of its theoretical characteristics and manipulation strategies in amino acid biosynthesis Jian-Zhong Xu, Han-Kun Yang & Wei-Guo Zhang To cite this article: Jian-Zhong Xu, Han-Kun Yang & Wei-Guo Zhang (2018): NADPH metabolism: a survey of its theoretical characteristics and manipulation strategies in amino acid biosynthesis, Critical Reviews in Biotechnology, DOI: 10.1080/07388551.2018.1437387 To link to this article: https://doi.org/10.1080/07388551.2018.1437387 Published online: 25 Feb 2018. Submit your article to this journal Article views: 7 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ibty20 CRITICAL REVIEWS IN BIOTECHNOLOGY, 2018 https://doi.org/10.1080/07388551.2018.1437387 REVIEW ARTICLE NADPH metabolism: a survey of its theoretical characteristics and manipulation strategies in amino acid biosynthesis Jian-Zhong Xua,b , Han-Kun Yanga and Wei-Guo Zhanga aThe Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, WuXi, PR China; bThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, WuXi, PR China ABSTRACT ARTICLE HISTORY Reduced nicotinamide adenine nucleotide phosphate (NADPH), which is one of the key cofactors Received 6 June 2017 in the metabolic network, plays an important role in the biochemical reactions, and physiological Revised 17 January 2018 function of amino acid-producing strains. The manipulation of NADPH availability and form is an Accepted 20 January 2018 efficient and easy method of redirecting the carbon flux to the amino acid biosynthesis in indus- KEYWORDS trial strains. In this review, we survey the metabolic mode of NADPH. Furthermore, we summarize NADPH; amino acid; the research developments in the understanding of the relationship between NADPH metabolism metabolic modes; and amino acid biosynthesis. Detailed strategies to manipulate NADPH availability are addressed manipulation strategies; based on this knowledge. Finally, the uses of NADPH manipulation strategies to enhance the biosynthetic pathway metabolic function of amino acid-producing strains are discussed. Introduction ADP), reduced-/nicotinamide adenine dinucleotide (NADH/NADþ), and reduced-/nicotinamide adenine Amino acids are types of organic compounds with carb- dinucleotide phosphate (NADPH/NADPþ) except for oxyl and amine groups that play important roles in reg- metabolic enzymes [4]. ATP and ADP are known as ulating the physiology of all life-forms. More than 300 energy cofactors, while NADH/NADþ and NADPH/ amino acids exist in nature, but only 20 of them are the þ basic structural elements of proteins, and only 10 are NADP are referred to as redox cofactors [5]. Figure 1 considered to be essential amino acids for humans and shows that these cofactors participate in the biosyn- animals [1]. In addition to the synthesis of proteins and thesis of several amino acids. Table S1 lists and numbers other compounds present in nature, amino acids also the enzymes involved in the three cofactor metabolism participate in a wide variety of biochemical reactions, for the metabolic pathways of E. coli and C. glutamicum. and are vital for energy transfer and energy cycles [2]. As one of the key cofactors in the metabolic network, The improvement of amino acid yield and efficiency has NADPH plays an important role in the biochemical reac- acquired significant interest because of the importance tions and physiological function of amino acid-produc- of amino acids in food, fodder, medical, cosmetic, and ing strains. Similar to other redox cofactors, NADPH is other industrial applications and the growing market also known as a co-enzyme in the cellular electron demand in the amino acid industry. At present, micro- transfer that drives the biosynthetic pathways of DNA, bial fermentation via Corynebacterium glutamicum or amino acids, fatty acids, phospholipids, and steroids. Escherichia coli plays a leading role in the amino acid Equally important is the universal reducing power of industry [3]. Appropriate strains and fermentation tech- NADPH to fuel the activities of enzymes, such as cata- nologies are crucial for amino acid production because lase, superoxide dismutase, and glutathione peroxidase, they promote increased carbon flux into the biosyn- which play important roles in allowing microorganisms thetic pathways of amino acids. However, the regulation to thrive in aerobic environments [6]. Moreover, NADH/ þ þ mechanism of these pathways is very complex because NAD generated from NADP can be used to form several metabolic reactions require the involvement of nicotinamide and other products, including ADP-ribose cofactors, such as adenosine tri-/di-phosphate (ATP/ (Figure 2)[6]. These metabolites can be employed as CONTACT Jian-Zhong Xu [email protected] The Key Laboratory of Industrial Biotechnology and The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, WuXi, PR China Supplemental data for this article can be accessed here. ß 2018 Informa UK Limited, trading as Taylor & Francis Group 2 J.-Z. XU ET AL. Glc 1 2 G6P 6PGlac 6PGluc 3 RL5P NADPH NADH ATP NADP NAD ADP F6P X5P R5P 51 PRPP His 52/53/54 4 S7P G3P F1,6BP DHAP GA3P E4P F6P 8 5 1,3BPG Tyr Cys 47/48 6 CHA 48 Phe 44/45/46 42 Ser 43 PHP 3PG Trp 49/50 Val Gly PEP 36 Ala 40 Asp 30 Asn 7 KIVal DHIV 35 Alac Pyr 31/32 41 9 Lac 12 13 14 29 33 Eth 13 AspSAld HSer KICap 34 HSerP AcCoA 10 36 DHDP Leu Cit OAA 37 Met Thr ICit 18 35 15 11 THDP Mal DHMV αKG 6 7 Fum SucAKP 36 1 Succ 1 9 1 38 Ile 39 Glu SucDAP 2 0 7 2 /2 / 1 6 2 Glu-γ-SAld AGlu-γ-SAld 25 LL-DAP 22 Spontaneous meso-DAP Arg α-AOrn Gln P5C Pro 28 23/24 Lys Figure 1. Metabolic pathways of NADPH and amino acids in E. coli and C. glutamicum. The abbreviations and the enzymes involved in the cofactor metabolism are listed in the Supplemental file and Table S1. The red lines (i.e. 19th–28th enzymatic reac- tions) indicate the biosynthetic pathway of GFAAs; the dark green lines (i.e. 29th–39th enzymatic reactions) indicate the biosyn- thetic pathway of AFAAs; the blue lines (i.e. 40th–41th enzymatic reactions) indicate the biosynthetic pathway of PFAAs; the pink lines (i.e. 42th–43th enzymatic reactions) indicate the biosynthetic pathway of SFAAs; and the spring-green lines (i.e. 44th–50th enzymatic reactions) indicate the biosynthetic pathway of AAAs. regulating factors to maintain cellular functions. Thus, their physiological functions are not the major emphasis NADPH plays an important part in cell growth and of this study [6,8]. The review aims to survey the meta- metabolite production. However, unlike other cofactors, bolic modes of NADPH and their relationship with NADPH drives anabolic reactions [7]. Although high- amino acid biosynthesis, and provide an overview of its producing amino acid strains were developed by applications. This review also covers strategies for manipulating the NADPH availability and state, given manipulating the NADPH availability and generating the existence of several reviews on the subject topic, amino acid-producing strains with a focus on two CRITICAL REVIEWS IN BIOTECHNOLOGY 3 NOX NADHK Electron transport chain ROS NADPH NADH ATP NADP+-dependent NAD+-dependent oxido-reductase oxido-reductase NAADP ARCs NADPase NADP+ NAD+ cADPRP NADK A + RCs, cARHs, LT ) P ase d AD( N ARTs PARPs dependent , e nucleosi Cs tc. ADPR(P) NAD- HD Poly(ADP-ribosyl- Deacetylation of Mono(ADP-ribosyl- ADP-ribose Regulating the ation) of protein (non-)histones protein ation) of protein cell function Figure 2. NADPH conversion and degradation. The abbreviations are listed in the Supplemental file. dominant organisms for industrial production of amino reversibly transferred by transhydrogenases between acids (i.e. C. glutamicum and E. coli) and the physio- NADH/NADþ and NADPH/NADPþ in several microorgan- logical consequences. isms. The Supplemental file presents in detail the enzymes involved in the NADPH anabolism and their characteristics. Table S2 summarizes the common NADPH metabolism enzymes involved in the NADPH regeneration and their þ The ratios of NADPH/NADP affects numerous enzym- properties. atic activities and endogenous concentrations of regula- tors (e.g. reactive oxygen species and nicotinic acid NADPH catabolism adenine dinucleotide phosphate) that play important roles in cellular functions and cell survival under several NADPH is an essential anabolic reducing cofactor in all conditions. Therefore, balancing the catabolic formation living organisms, which is involved in numerous ana- of NADPH with the anabolic demand is crucial to amino bolic reactions to form NADPþ. Wittmann and de Graaf acid biosynthesis via microbial fermentation. [14] identified that the formation of 1 g of biomass requires 16.4 mmol of NADPH to form NADPþ. Thus, NADPH catabolism is closely related to the biomass for- NADPH anabolism mation rate, which will significantly vary with the envir- The following are three major methods by which onmental conditions [7]. Most of the NADPH is NADPH can be formed (Figure 3): I) NADPH is regener- consumed by an NADPH-dependent reductase to form þ þ ated from NADP by diversified NADP -dependent NADPþ as the hydride transfer is finally completed. þ enzymes; II) NADPH is regenerated from NAD using However, the intracellular level of NADPþ is lower than þ NAD kinases, or from NADH using NADH kinases; and its theoretical value because NADPþ can be catabolized þ III) NADPH is regenerated from NADH and NADP using by multiple families of enzymes to form different transhydrogenases. Method I is the major method for nucleotide derivatives and other products including NADPH-regeneration in glucose-grown microorganism ADP-ribose (Figure 2)[15].
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