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    					Cofactor engineering in cyanobacteria to overcome imbalance between NADPH and NADH: A mini review  | 
  					 
  					  										
						Jongmoon Park1,2,3,Yunnam Choi1( ) | 
					 
															
						1. Department of Chemical Engineering, Pohang University of Science and Technology, Gyeongbuk 790-784, Korea 2. School of Environmental Science and Engineering, Pohang University of Science and Technology, Gyeongbuk 790-784, Korea 3. Division of Advanced Nuclear Engineering, Pohang University of Science and Technology, Gyeongbuk 790-784, Korea | 
					 
										
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													     		                            						                            																	    Abstract  Cyanobacteria can produce useful renewable fuels and high-value chemicals using sunlight and atmospheric carbon dioxide by photosynthesis. Genetic manipulation has increased the variety of chemicals that cyanobacteria can produce. However, their uniquely abundant NADPH-pool, in other words insufficient supply of NADH, tends to limit their production yields in case of utilizing NADH-dependent enzyme, which is quite common in heterotrophic microbes. To overcome this cofactor imbalance and enhance cyanobacterial fuel and chemical production, various approaches for cofactor engineering have been employed. In this review, we focus on three approaches: (1) utilization of NADPH-dependent enzymes, (2) increasing NADH production, and (3) changing cofactor specificity of NADH-dependent enzymes from NADH to NADPH. 
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															| Keywords 
																																																				NADH-dependent enzyme  
																		  																																				NADPH-dependent enzyme  
																		  																																				transhydrogenase  
																		  																																				site-directed mutagenesis  
																		  																																				enzyme engineering  
																																			  
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																																Corresponding Author(s):
																Yunnam Choi   
																													     		
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																															Just Accepted Date: 19 August 2016  
																																														Online First Date: 18 September 2016   
																																														Issue Date: 17 March 2017
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															| 1 | 
															 
														     Parmar A, Singh N K, Pandey A, Gnansounou E, Madamwar D. Cyanobacteria and microalgae: A positive prospect for biofuels. Bioresource Technology, 2011, 102(22): 10163–10172
														     														     	 
														     															     		https://doi.org/10.1016/j.biortech.2011.08.030
														     															     															     															 | 
																  
																														
															| 2 | 
															 
														     Machado I M, Atsumi S. Cyanobacterial biofuel production. Journal of Biotechnology, 2012, 162(1): 50–56
														     														     	 
														     															     		https://doi.org/10.1016/j.jbiotec.2012.03.005
														     															     															     															 | 
																  
																														
															| 3 | 
															 
														     Nozzi N E, Oliver J W, Atsumi S. Cyanobacteria as a platform for biofuel production. Frontiers in Bioengineering and Biotechnology, 2013, 1: 1–6
														     														     	 
														     															     		https://doi.org/10.3389/fbioe.2013.00007
														     															     															     															 | 
																  
																														
															| 4 | 
															 
														     Deng M D, Coleman J R. Ethanol synthesis by genetic engineering in cyanobacteria. Applied and Environmental Microbiology, 1999, 65(2): 523–528
														     															 | 
																  
																														
															| 5 | 
															 
														     Dexter J, Fu P. Metabolic engineering of cyanobacteria for ethanol production. Energy & Environmental Science, 2009, 2(8): 857–864
														     														     	 
														     															     		https://doi.org/10.1039/b811937f
														     															     															     															 | 
																  
																														
															| 6 | 
															 
														     Gao Z, Zhao H, Li Z, Tan X, Lu X. Photosynthetic production of ethanol from carbon dioxide in genetically engineered cyanobacteria. Energy & Environmental Science, 2012, 5(12): 9857–9865
														     														     	 
														     															     		https://doi.org/10.1039/C2EE22675H
														     															     															     															 | 
																  
																														
															| 7 | 
															 
														     Choi Y N, Park J M. Enhancing biomass and ethanol production by increasing NADPH production in Synechocystis sp. PCC 6803. Bioresource Technology, 2016, 213: 54–57
														     														     	 
														     															     		https://doi.org/10.1016/j.biortech.2016.02.056
														     															     															     															 | 
																  
																														
															| 8 | 
															 
														     Kusakabe T, Tatsuke T, Tsuruno K, Hirokawa Y, Atsumi S, Liao J C, Hanai T. Engineering a synthetic pathway in cyanobacteria for isopropanol production directly from carbon dioxide and light. Metabolic Engineering, 2013, 20: 101–108
														     														     	 
														     															     		https://doi.org/10.1016/j.ymben.2013.09.007
														     															     															     															 | 
																  
																														
															| 9 | 
															 
														     Lan E I, Liao J C. Metabolic engineering of cyanobacteria for 1-butanol production from carbon dioxide. Metabolic Engineering, 2011, 13(4): 353–363
														     														     	 
														     															     		https://doi.org/10.1016/j.ymben.2011.04.004
														     															     															     															 | 
																  
																														
															| 10 | 
															 
														     Lan E I, Liao J C. ATP drives direct photosynthetic production of 1-butanol in cyanobacteria. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(16): 6018–6023
														     														     	 
														     															     		https://doi.org/10.1073/pnas.1200074109
														     															     															     															 | 
																  
																														
															| 11 | 
															 
														     Atsumi S, Higashide W, Liao J C. Direct photosynthetic recycling of carbon dioxide to isobutyraldehyde. Nature Biotechnology, 2009, 27(12): 1177–1180
														     														     	 
														     															     		https://doi.org/10.1038/nbt.1586
														     															     															     															 | 
																  
																														
															| 12 | 
															 
														     Angermayr S A, Paszota M, Hellingwerf K J. Engineering a cyanobacterial cell factory for production of lactic acid. Applied and Environmental Microbiology, 2012, 78(19): 7098–7106
														     														     	 
														     															     		https://doi.org/10.1128/AEM.01587-12
														     															     															     															 | 
																  
																														
															| 13 | 
															 
														     Varman A M, Yu Y, You L, Tang Y J. Photoautotrophic production of D-lactic acid in an engineered cyanobacterium. Microbial Cell Factories, 2013, 12(1): 1–8
														     														     	 
														     															     		https://doi.org/10.1186/1475-2859-12-117
														     															     															     															 | 
																  
																														
															| 14 | 
															 
														     Zhou J, Zhang H, Meng H, Zhang Y, Li Y. Production of optically pure D-lactate from CO2 by blocking the PHB and acetate pathways and expressing D-lactate dehydrogenase in cyanobacterium Synechocystis sp. PCC 6803. Process Biochemistry, 2014, 49(12): 2071–2077
														     														     	 
														     															     		https://doi.org/10.1016/j.procbio.2014.09.007
														     															     															     															 | 
																  
																														
															| 15 | 
															 
														     Angermayr S A, Van der Woude A D, Correddu D, Vreugdenhil A, Verrone V, Hellingwerf K J. Exploring metabolic engineering design principles for the photosynthetic production of lactic acid by Synechocystis sp. PCC6803. Biotechnology for Biofuels, 2014, 7(1): 1–15
														     														     	 
														     															     		https://doi.org/10.1186/1754-6834-7-99
														     															     															     															 | 
																  
																														
															| 16 | 
															 
														     Li C, Tao F, Ni J, Wang Y, Yao F, Xu P. Enhancing the light-driven production of D-lactate by engineering cyanobacterium using a combinational strategy. Scientific Reports, 2015, 5: 1–11
														     															 | 
																  
																														
															| 17 | 
															 
														     Miyake M, Takase K, Narato M, Khatipov E, Schnackenberg J, Shirai M, Kurane R, Asada Y. Polyhydroxybutyrate production from carbon dioxide by cyanobacteria. Applied Biochemistry and Biotechnology, 2000, 84-86(1-9): 991–1002
														     														     	 
														     															     		https://doi.org/10.1385/ABAB:84-86:1-9:991
														     															     															     															 | 
																  
																														
															| 18 | 
															 
														     Tyo K E, Jin Y S, Espinoza F A, Stephanopoulos G. Identification of gene disruptions for increased poly-3-hydroxybutyrate accumulation in Synechocystis PCC 6803. Biotechnology Progress, 2009, 25(5): 1236–1243
														     														     	 
														     															     		https://doi.org/10.1002/btpr.228
														     															     															     															 | 
																  
																														
															| 19 | 
															 
														     Zhou J, Zhu T, Cai Z, Li Y. From cyanochemicals to cyanofactories: A review and perspective. Microbial Cell Factories, 2016, 15(1): 1–9
														     														     	 
														     															     		https://doi.org/10.1186/s12934-015-0405-3
														     															     															     															 | 
																  
																														
															| 20 | 
															 
														     Wang Y, San K Y, Bennett G N. Cofactor engineering for advancing chemical biotechnology. Current Opinion in Biotechnology, 2013, 24(6): 994–999, 99
														     														     	 
														     															     		https://doi.org/10.1016/j.copbio.2013.03.022
														     															     															     															 | 
																  
																														
															| 21 | 
															 
														     Akhtar M K, Jones P R. Cofactor Engineering for enhancing the flux of metabolic pathways. Frontiers in Bioengineering and Biotechnology, 2014, 2: 1–6
														     														     	 
														     															     		https://doi.org/10.3389/fbioe.2014.00030
														     															     															     															 | 
																  
																														
															| 22 | 
															 
														     Tamoi M, Miyazaki T, Fukamizo T, Shigeoka S. The calvin cycle in cyanobacteria is regulated by CP12 via the NAD(H)/NADP(H) ratio under light/dark conditions. Plant Journal, 2005, 42(4): 504–513
														     														     	 
														     															     		https://doi.org/10.1111/j.1365-313X.2005.02391.x
														     															     															     															 | 
																  
																														
															| 23 | 
															 
														     Cooley J W, Vermaas W F. Succinate dehydrogenase and other respiratory pathways in thylakoid membranes of Synechocystis sp. strain PCC 6803: Capacity comparisons and physiological function. Journal of Bacteriology, 2001, 183(14): 4251–4258
														     														     	 
														     															     		https://doi.org/10.1128/JB.183.14.4251-4258.2001
														     															     															     															 | 
																  
																														
															| 24 | 
															 
														     Dempo Y, Ohta E, Nakayama Y, Bamba T, Fukusaki E. Molar-based targeted metabolic profiling of cyanobacterial strains with potential for biological production. Metabolites, 2014, 4(2): 499–516
														     														     	 
														     															     		https://doi.org/10.3390/metabo4020499
														     															     															     															 | 
																  
																														
															| 25 | 
															 
														     Hirokawa Y, Maki Y, Tatsuke T, Hanai T. Cyanobacterial production of 1,3-propanediol directly from carbon dioxide using a synthetic metabolic pathway. Metabolic Engineering, 2016, 34: 97–103
														     														     	 
														     															     		https://doi.org/10.1016/j.ymben.2015.12.008
														     															     															     															 | 
																  
																														
															| 26 | 
															 
														     Li H, Liao J C. Engineering a cyanobacterium as the catalyst for the photosynthetic conversion of CO2 to 1,2-propanediol. Microbial Cell Factories, 2013, 12(1): 1–9
														     														     	 
														     															     		https://doi.org/10.1186/1475-2859-12-4
														     															     															     															 | 
																  
																														
															| 27 | 
															 
														     Oliver J W, Machado I M, Yoneda H, Atsumi S. Cyanobacterial conversion of carbon dioxide to 2,3-butanediol. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(4): 1249–1254
														     														     	 
														     															     		https://doi.org/10.1073/pnas.1213024110
														     															     															     															 | 
																  
																														
															| 28 | 
															 
														     Savakis P E, Angermayr S A, Hellingwerf K J. Synthesis of 2,3-butanediol by Synechocystis sp. PCC 6803 via heterologous expression of a catabolic pathway from lactic acid-and enterobacteria. Metabolic Engineering, 2013, 20: 121–130
														     														     	 
														     															     		https://doi.org/10.1016/j.ymben.2013.09.008
														     															     															     															 | 
																  
																														
															| 29 | 
															 
														     Niederholtmeyer H, Wolfstadter B T, Savage D F, Silver P A, Way J C. Engineering cyanobacteria to synthesize and export hydrophilic products. Applied and Environmental Microbiology, 2010, 76(11): 3462–3466
														     														     	 
														     															     		https://doi.org/10.1128/AEM.00202-10
														     															     															     															 | 
																  
																														
															| 30 | 
															 
														     McNeely K, Xu Y, Bennette N, Bryant D A, Dismukes G C. Redirecting reductant flux into hydrogen production via metabolic engineering of fermentative carbon metabolism in a cyanobacterium. Applied and Environmental Microbiology, 2010, 76(15): 5032–5038
														     														     	 
														     															     		https://doi.org/10.1128/AEM.00862-10
														     															     															     															 | 
																  
																														
															| 31 | 
															 
														     Kumaraswamy G K, Guerra T, Qian X, Zhang S, Bryant D A, Dismukes G C. Reprogramming the glycolytic pathway for increased hydrogen production in cyanobacteria: Metabolic engineering of NAD+-dependent GAPDH. Energy & Environmental Science, 2013, 6(12): 3722–3731
														     														     	 
														     															     		https://doi.org/10.1039/c3ee42206b
														     															     															     															 | 
																  
																														
															| 32 | 
															 
														     Jarboe L R, Yqh D. A broad-substrate range aldehyde reductase with various applications in production of biorenewable fuels and chemicals. Applied Microbiology and Biotechnology, 2011, 89(2): 249–257
														     														     	 
														     															     		https://doi.org/10.1007/s00253-010-2912-9
														     															     															     															 | 
																  
																														
															| 33 | 
															 
														     Wee Y J, Kim J N, Ryu H W. Biotechnological production of lactic acid and its recent applications. Food Technology and Biotechnology, 2006, 44(2): 163–172
														     															 | 
																  
																														
															| 34 | 
															 
														     Joseph A, Aikawa S, Sasaki K, Tsuge Y, Matsuda F, Tanaka T, Kondo A. Utilization of lactic acid bacterial genes in Synechocystis sp. PCC 6803 in the production of lactic acid. Bioscience, Biotechnology, and Biochemistry, 2013, 77(5): 966–970
														     														     	 
														     															     		https://doi.org/10.1271/bbb.120921
														     															     															     															 | 
																  
																														
															| 35 | 
															 
														     Polizzi K M, Chaparro-Riggers J F, Vazquez-Figueroa E, Bommarius A S. Structure-guided consensus approach to create a more thermostable penicillin G acylase. Biotechnology Journal, 2006, 1(5): 531–536
														     														     	 
														     															     		https://doi.org/10.1002/biot.200600029
														     															     															     															 | 
																  
																														
															| 36 | 
															 
														     Terao Y, Miyamoto K, Ohta H. Introduction of single mutation changes arylmalonate decarboxylase to racemase. Chemical Communications, 2006, 34(34): 3600–3602
														     														     	 
														     															     		https://doi.org/10.1039/b607211a
														     															     															     															 | 
																  
																														
															| 37 | 
															 
														     Vázquez-Figueroa E, Chaparro-Riggers J, Bommarius A S. Development of a thermostable glucose dehydrogenase by a structure-guided consensus concept. ChemBioChem, 2007, 8(18): 2295–2301
														     														     	 
														     															     		https://doi.org/10.1002/cbic.200700500
														     															     															     															 | 
																  
																														
															| 38 | 
															 
														     Jochens H, Bornscheuer U T. Natural diversity to guide focused directed evolution. ChemBioChem, 2010, 11(13): 1861–1866
														     														     	 
														     															     		https://doi.org/10.1002/cbic.201000284
														     															     															     															 | 
																  
																														
															| 39 | 
															 
														     Ema T, Nakano Y, Yoshida D, Kamata S, Sakai T. Redesign of enzyme for improving catalytic activity and enantioselectivity toward poor substrates: Manipulation of the transition state. Organic & Biomolecular Chemistry, 2012, 10(31): 6299–6308
														     														     	 
														     															     		https://doi.org/10.1039/c2ob25614b
														     															     															     															 | 
																  
																														
															| 40 | 
															 
														     Holmberg N, Ryde U, Bulow L. Redesign of the coenzyme specificity in L-lactate dehydrogenase from bacillus stearothermophilus using site-directed mutagenesis and media engineering. Protein Engineering, Design & Selection, 1999, 12(10): 851–856
														     														     	 
														     															     		https://doi.org/10.1093/protein/12.10.851
														     															     															     															 | 
																  
																														
															| 41 | 
															 
														     Ma C, Zhang L, Dai J, Xiu Z. Relaxing the coenzyme specificity of 1,3-propanediol oxidoreductase from Klebsiella pneumoniae by rational design. Journal of Biotechnology, 2010, 146(4): 173–178
														     														     	 
														     															     		https://doi.org/10.1016/j.jbiotec.2010.02.005
														     															     															     															 | 
																  
																														
															| 42 | 
															 
														     Richter N, Zienert A, Hummel W. A single-point mutation enables lactate dehydrogenase from Bacillus subtilis to utilize NAD+ and NADP+ as cofactor. Engineering in Life Sciences, 2011, 11(1): 26–36
														     														     	 
														     															     		https://doi.org/10.1002/elsc.201000151
														     															     															     															 | 
																  
																														
															| 43 | 
															 
														     Meng H, Liu P, Sun H, Cai Z, Zhou J, Lin J, Li Y. Engineering a D-lactate dehydrogenase that can super-efficiently utilize NADPH and NADH as cofactors. Scientific Reports, 2016, 6: 1–8
														     															 | 
																  
																														
															| 44 | 
															 
														     Steiner K, Schwab H. Recent advances in rational approaches for enzyme engineering. Computational and Structural Biotechnology Journal, 2012, 2(3): 1–12
														     														     	 
														     															     		https://doi.org/10.5936/csbj.201209010
														     															     															     															 | 
																  
																														
															| 45 | 
															 
														     Li Y, Cirino P C. Recent advances in engineering proteins for biocatalysis. Biotechnology and Bioengineering, 2014, 111(7): 1273–1287
														     														     	 
														     															     		https://doi.org/10.1002/bit.25240
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