Abstract
Threats to stable oil supplies and concerns over environmental emissions have pushed for renewable biofuel developments to minimize dependence on fossil resources. Recent biofuel progress has moved towards fossil resource-independent carbon cycles, but environmental issues regarding use of nitrogen fertilizers have not been addressed on a global scale. The recently demonstrated conversion of waste protein biomass into advanced biofuels and renewable chemicals, while recycling nitrogen fertilizers, offers a glimpse of the efforts needed to balance the nitrogen cycle at scale. In general, the catabolism of protein into biofuels is challenging because of physiological regulation and thermodynamic limitations. This conversion became possible with metabolic engineering around ammonia assimilation, intracellular nitrogen flux, and quorum sensing. This review highlights the metabolic engineering solutions in transforming those cellular processes into driving forces for the high yield of chemical products from protein.
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Ajikumar PK, Xiao WH, Tyo KE, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G (2010) Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science 330:70–74. doi:10.1126/science.1191652
Atsumi S, Cann AF, Connor MR, Shen CR, Smith KM, Brynildsen MP, Chou KJ, Hanai T, Liao JC (2008a) Metabolic engineering of Escherichia coli for 1-butanol production. Metab Eng 10:305–311. doi:10.1016/j.ymben.2007.08.003
Atsumi S, Hanai T, Liao JC (2008b) Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels. Nature 451:86–89. doi:10.1038/nature06450
Atsumi S, Wu TY, Eckl EM, Hawkins SD, Buelter T, Liao JC (2010) Engineering the isobutanol biosynthetic pathway in Escherichia coli by comparison of three aldehyde reductase/alcohol dehydrogenase genes. Appl Microbiol Biotechnol 85:651–657. doi:10.1007/s00253-009-2085-6
Bastian S, Liu X, Meyerowitz JT, Snow CD, Chen MM, Arnold FH (2011) Engineered ketol-acid reductoisomerase and alcohol dehydrogenase enable anaerobic 2-methylpropan-1-ol production at theoretical yield in Escherichia coli. Metab Eng 13:345–352. doi:10.1016/j.ymben.2011.02.004
Basu S, Gerchman Y, Collins CH, Arnold FH, Weiss R (2005) A synthetic multicellular system for programmed pattern formation. Nature 434:1130–1134. doi:10.1038/nature03461
Brenner K, You L, Arnold FH (2008) Engineering microbial consortia: a new frontier in synthetic biology. Trends Biotechnol 26:483–489. doi:10.1016/j.tibtech.2008.05.004
Cann AF, Liao JC (2008) Production of 2-methyl-1-butanol in engineered Escherichia coli. Appl Microbiol Biotechnol 81:89–98. doi:10.1007/s00253-008-1631-y
Caspi R, Altman T, Dreher K, Fulcher CA, Subhraveti P, Keseler IM, Kothari A, Krummenacker M, Latendresse M, Mueller LA, Ong Q, Paley S, Pujar A, Shearer AG, Travers M, Weerasinghe D, Zhang P, Karp PD (2012) The MetaCyc Database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res 40:742–753. doi:10.1093/nar/gkr1014
Chang MC, Keasling JD (2006) Production of isoprenoid pharmaceuticals by engineered microbes. Nat Chem Biol 2:674–681. doi:10.1038/nchembio836
Cho BK, Seo JH, Kang TW, Kim BG (2003) Asymmetric synthesis of l-homophenylalanine by equilibrium-shift using recombinant aromatic l-amino acid transaminase. Biotechnol Bioeng 83:226–234. doi:10.1002/bit.10661
Choi O, Um Y, Sang BI (2012) Butyrate production enhancement by Clostridium tyrobutyricum using electron mediators and a cathodic electron donor. Biotechnol Bioeng 109:2494–2502. doi:10.1002/bit.24520
Connor MR, Liao JC (2009) Microbial production of advanced transportation fuels in non-natural hosts. Curr Opin Biotechnol 20:307–315. doi:10.1016/j.copbio.2009.04.002
Connor MR, Cann AF, Liao JC (2010) 3-Methyl-1-butanol production in Escherichia coli: random mutagenesis and two-phase fermentation. Appl Microbiol Biotechnol 86:1155–1164. doi:10.1007/s00253-009-2401-1
Crutzen PJ, Mosier AR, Smith KA, Winiwarter W (2008) N2O release from agro-biofuel production negates global warming reduction by replacing fossil fuels. Atmos Chem Phys 8:389–395
Dela Vega AL, Delcour AH (1996) Polyamines decrease Escherichia coli outer membrane permeability. J Bacteriol 178:3715–3721
Dellomonaco C, Clomburg JM, Miller EN, Gonzalez R (2011) Engineered reversal of the beta-oxidation cycle for the synthesis of fuels and chemicals. Nature 476:355–359. doi:10.1038/nature10333
Draths KM, Frost JW (1994) Environmentally compatible synthesis of adipic acid from d-glucose. J Am Chem Soc 116:399–400. doi:10.1021/ja00080a057
Dunlop MJ, Dossani ZY, Szmidt HL, Chu HC, Lee TS, Keasling JD, Hadi MZ, Mukhopdhyay A (2011) Engineering microbial biofuel tolerance and export using efflux pumps. Mol Syst Biol 7:487. doi:10.1038/msb.2011.21
Erisman JW, Sutton MA, Galloway J, Klimont Z, Winiwarter W (2008) How a century of ammonia synthesis changed the world. Nat Geosci 1:636–639
Fuqua C, Parsek MR, Greenberg EP (2001) Regulation of gene expression by cell-to-cell communication: Acyl-homoserine lactone quorum sensing. Annu Rev Genet 35:439–468. doi:10.1146/annurev.genet.35.102401.090913
Garcia-Ojalvo J, Elowitz MB, Strogatz SH (2004) Modeling a synthetic multicellular clock: repressilators coupled by quorum sensing. Proc Natl Acad Sci USA 101:10955–10960. doi:10.1073/pnas.0307095101
Gutierrez RA (2012) Systems biology for enhanced plant nitrogen nutrition. Science 336:1673–1675. doi:10.1126/science.1217620
Hazelwood LA, Daran JM, van Maris AJ, Pronk JT, Dickinson JR (2008) The Ehrlich pathway for fusel alcohol production: a century of research on Saccharomyces cerevisiae metabolism. Appl Environ Microbiol 74:2259–2266. doi:10.1128/AEM.02625-07
Huo YX, Cho KM, Rivera JGL, Monte E, Shen CR, Yan YJ, Liao JC (2011) Conversion of proteins into biofuels by engineering nitrogen flux. Nat Biotechnol 29:346–351. doi:10.1038/nbt.1789
Huo YX, Wernick DG, Liao JC (2012) Toward nitrogen neutral biofuel production. Curr Opin Biotechnol 23:406–413. doi:10.1016/j.copbio.2011.10.005
Jang YS, Park JM, Choi S, Choi YJ, Seung DY, Cho JH, Lee SY (2011) Engineering of microorganisms for the production of biofuels and perspectives based on systems metabolic engineering approaches. Biotechnol Adv 30:989–1000. doi:10.1016/j.biotechadv.2011.08.015
Jarboe LR, Zhang X, Wang X, Moore JC, Shanmugam KT, Ingram LO (2010) Metabolic engineering for production of biorenewable fuels and chemicals: contributions of synthetic biology. J Biomed Biotechnol. doi:10.1155/2010/761042
Jarboe LR, Liu P, Royce LA (2011) Engineering inhibitor tolerance for the production of biorenewable fuels and chemicals. Curr Opin Chem Eng 1:38–42. doi:10.1016/j.coche.2011.08.003
Kearns DB, Venot A, Bonner PJ, Stevens B, Boons GJ, Shimkets LJ (2001) Identification of a developmental chemoattractant in Myxococcus xanthus through metabolic engineering. Proc Natl Acad Sci USA 98:13990–13994. doi:10.1073/pnas.251484598
Keseler IM, Collado-Vides J, Santos-Zavaleta A, Peralta-Gil M, Gama-Castro S, Muniz-Rascado L, Bonavides-Martinez C, Paley S, Krummenacker M, Altman T, Kaipa P, Spaulding A, Pacheco J, Latendresse M, Fulcher C, Sarker M, Shearer AG, Mackie A, Paulsen I, Gunsalus R, Karp PD (2011) EcoCyc: a comprehensive database of Escherichia coli biology. Nucleic Acids Res 39:583–590. doi:10.1093/nar/gkq1143
Kim S, Dale BE (2005) Environmental aspects of ethanol derived from no-tilled corn grain: nonrenewable energy consumption and greenhouse gas emissions. Biomass Bioenergy 25:475–489. doi:10.1016/j.biombioe.2004.11.005
Kleerebezem M, Quadri LE, Kuipers OP, de Vos WM (1997) Quorum sensing by peptide pheromones and two-component signal-transduction systems in gram-positive bacteria. Mol Microbiol 24:895–904
Knobeloch L, Salna B, Hogan A, Postle J, Anderson H (2000) Blue babies and nitrate-contaminated well water. Environ Health Perspect 108:675–678
Koma D, Yamanaka H, Moriyoshi K, Ohmoto T, Sakai K (2012) Production of aromatic compounds by metabolically engineered Escherichia coli with an expanded shikimate pathway. Appl Environ Microbiol 78:6203–6216. doi:10.1128/AEM.01148-12
Kreimeyer A, Perret A, Lechaplais C, Vallenet D, Medigue C, Salanoubat M, Weissenbach J (2007) Identification of the last unknown genes in the fermentation pathway of lysine. J Biol Chem 282:7191–7197. doi:10.1074/jbc.M609829200
Lammens TM, Franssen MCR, Scott EL, Sanders JPM (2010) Synthesis of biobased N-methylpyrrolidone by one-pot cyclization and methylation of γ-aminobutyric acid. Green Chem 12:1430–1436. doi:10.1039/C0GC00061B
Lammens TM, Franssen MCR, Scott EL, Sanders JPM (2012) Availability of protein-derived amino acids as feedstock for the production of bio-based chemicals. Biomass Bioenergy 44:168–181. doi:10.1016/j.biombioe.2012.04.021
Lamsen EN, Atsumi S (2012) Recent progress in synthetic biology for microbial production of C3-C10 alcohols. Front Microbiol 3:196–201. doi:10.3389/fmicb.2012.00196
Lan EI, Liao JC (2012) ATP drives direct photosynthetic production of 1-butanol in cyanobacteria. Proc Natl Acad Sci USA 109:6018–6023. doi:10.1073/pnas.1200074109
Lazazzera BA (2000) Quorum sensing and starvation: signals for entry into stationary phase. Curr Opin Microbiol 3:177–182. doi:10.1016/S1369-5274(00)00072-2
Li H, Opgenorth OH, Wernick DG, Rogers S, Wu TY, Higashide W, Malati P, Huo YX, Cho KM, Liao JC (2012) Integrated electromicrobial conversion of CO2 to higher alcohols. Science 335:1596–1596. doi:10.1126/science.1217643
Lopez de Felipe F, Kleerebezem M, de Vos WM, Hugenholtz J (1998) Cofactor engineering: a novel approach to metabolic engineering in Lactococcus lactis by controlled expression of NADH oxidase. J Bacteriol 180:3804–3808
Machado IM, Atsumi S (2012) Cyanobacterial biofuel production. J Biotechnol 162:50–56. doi:10.1016/j.jbiotec.2012.03.005
Mainguet SE, Liao JC (2010) Bioengineering of microorganisms for C3 to C5 alcohols production. Biotechnology J5:1297–1308. doi:10.1002/biot.201000276
Marcheschi RJ, Li H, Zhang K, Noey EL, Kim S, Chaubey A, Houk KN, Liao JC (2012) A synthetic recursive “+1” pathway for carbon chain elongation. ACS Chem Biol 7:689–697. doi:10.1021/cb200313e
Martinez A, Grabar TB, Shanmugan KT, Yomano LP, York SW, Ingram LO (2007) Low salt medium for lactate and ethanol production by recombinant Escherichia coli B. Biotechnol Lett 28:397–404
Mckenna R, Nielsen DR (2011) Styrene biosynthesis from glucose by engineered Escherichia coli. Metab Eng 13:544–554. doi:10.1016/j.ymben.2011.06.005
Miller SA (2010) Minimizing land use and nitrogen intensity of bioenergy. Environ Sci Technol 44:3932–3939. doi:10.1021/es902405a
Montzka SA, Dlugokencky EJ, Butler JH (2011) Non-CO2 greenhouse gases and climate change. Nature 476:43–50. doi:10.1038/nature10322
Muranova TA, Ruzheinikov SN, Sedelnikova SE, Baker PJ, Pasquo A, Galkin A, Esaki N, Ohshima T, Soda K, Rice DW (2002) Crystallization and preliminary X-ray analysis of substrate complexes of leucine dehydrogenase from Thermoactinomyces intermedius. Acta Crystallogr 58:1059–1062
Ohshima T, Nishida N, Bakthavatsalam S, Kataoka K, Takada H, Yoshimura T, Esaki N, Soda K (1994) The purification, characterization, cloning and sequencing of the gene for a halostable and thermostable leucine dehydrogenase from Thermoactinomyces intermedius. Eur J Biochem 222:305–312
Ohta K, Beall DS, Mejia JP, Shanmugan KT, Ingram LO (1991) Genetic improvement of Escherichia coli for ethanol production: chromosomal integration of Zymomonas mobilis genes encoding pyruvate decarboxylase and alcohol dehydrogenase II. Appl Environ Microbiol 57:893–900
Okabe M, Lies D, Kanamasa S, Park EY (2009) Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl Microbiol Biotechnol 84:597–606. doi:10.1007/s00253-009-2132-3
Paerl HW, Scott JT (2010) Throwing fuel on the fire: synergistic effects of excessive nitrogen inputs and global warming on harmful algal blooms. Environ Sci Technol 44:7756–7758. doi:10.1021/es102665e
Peralta-Yahya PP, Zhang F, del Cardayre SB, Keasling JD (2012) Microbial engineering for the production of advanced biofuels. Nature 488:320–328. doi:10.1038/nature11478
Radakovits R, Jinkerson RE, Darzins A, Posewitz MC (2010) Genetic engineering of algae for enhanced biofuel production. Eukaryot Cell 9:486–501. doi:10.1128/EC.00364-09
Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–943. doi:10.1038/nature04640
San KY, Bennett GN, Berrios-Rivera SJ, Vadali RV, Yang YT, Horton E, Rudolph FB, Sariyar B, Blackwood K (2002) Metabolic engineering through cofactor manipulation and its effects on metabolic flux redistribution in Escherichia coli. Metab Eng 4:182–192
Satoh Y, Tajima K, Munekata M, Keasling JD, Lee TS (2012) Engineering of a tyrosol-producing pathway, utilizing simple sugar and the central metabolic tyrosine, in Escherichia coli. J Agric Food Chem 60:979–984. doi:10.1021/jf203256f
Schirmer A, Rude MA, Li X, Popova E, del Cardayre SB (2010) Microbial biosynthesis of alkanes. Science 329:559–562. doi:10.1126/science.1187936
Shen CR, Liao JC (2008) Metabolic engineering of Escherichia coli for 1-butanol and 1-propanol production via the keto-acid pathways. Metab Eng 10:312–320. doi:10.1016/j.ymben.2008.08.001
Shen CR, Lan EI, Dekishima Y, Baez A, Cho KM, Liao JC (2011) Driving forces enable high-titer anaerobic 1-butanol synthesis in Escherichia coli. Appl Environ Microbiol 77:2905–2915. doi:10.1128/AEM.03034-10
Shimazaki J, Furukawa S, Ogihara H, Morinaga Y (2012) l-Tryptophan prevents Escherichia coli biofilm formation and triggers biofilm degradation. Biochem Biophys Res Commun 419:715–718. doi:10.1016/j.bbrc.2012.02.085
Steen EJ, Kang Y, Bokinsky G, Hu Z, Schirmer A, McClure A, Del Cardayre SB, Keasling JD (2009) Microbial production of fatty-acid-derived fuels and chemicals from plant biomass. Nature 463:559–562
Su H, Newman EB (1991) A novel l-serine deaminase activity in Escherichia coli K-12. J Bacteriol 173:2473–2480
Surette MG, Bassler BL (1998) Quorum sensing in Escherichia coli and Salmonella typhimurium. Proc Natl Acad Sci USA 95:7046–7050
Taheripour F, Hertel TW, Tyner WE, Beckman JF, Birur DK (2010) Biofuels and their by-products: global economic and environmental implications. Biomass Bioenergy 34:278–289
Van Dien SJB AP, Haselbeck R, Pujol-baxely CJ, Niu, W, Trawick JD, Burk MJ, Osterhout RE, Sun, J (2012) Microorganisms for the production of 1,4-butanediol and related methods. Genomatica, Inc US Patent Application 20120225463
van Leeuwen BN, van der Wulp AM, Duijnstee I, van Maris AJ, Straathof AJ (2012) Fermentative production of isobutene. Appl Microbiol Biotechnol 93:1377–1387. doi:10.1007/s00253-011-3853-7
Vendeville A, Winzer K, Heurlier K, Tang CM, Hardie KR (2005) Making ‘sense’ of metabolism: autoinducer-2, LUXS and pathogenic bacteria. Nat Rev Microbiol 3:383–396. doi:10.1038/nrmicro1148
Waters CM, Bassler BL (2005) Quorum sensing: cell-to-cell communication in bacteria. Annu Rev Cell Dev Biol 21:319–346. doi:10.1146/annurev.cellbio.21.012704.131001
Wehrli B (2011) Climate science renewable but not carbon-free. Nat Geosci 4:585–586. doi:10.1038/Ngeo1226
Weiland P (2010) Biogas production: current state and perspectives. Appl Microbiol Biotechnol 85:849–860. doi:10.1007/s00253-009-2246-7
Whalen WA, Berg CM (1982) Analysis of an avtA::Mu d1(Ap lac) mutant: metabolic role of transaminase C. J Bacteriol 150:739–746
Wild J, Klopotowski T (1981) d-Amino acid dehydrogenase of Escherichia coli K12: positive selection of mutants defective in enzyme activity and localization of the structural gene. Mol Gen Genet 181:373–378
Xiong M, Deng J, Woodruff AP, Zhu M, Zhou J, Park SW, Li H, Fu Y, Zhang K (2012) A bio-catalytic approach to aliphatic ketones. Sci Rep 2:311. doi:10.1038/srep00311
Xiu ZL, Zeng AP (2008) Present state and perspective of downstream processing of biologically produced 1,3-propanediol and 2,3-butanediol. Appl Microbiol Biotechnol 78:917–926. doi:10.1007/s00253-008-1387-4
Zha W, Shao Z, Frost JW, Zhao H (2004) Rational pathway engineering of type I fatty acid synthase allows the biosynthesis of triacetic acid lactone from d-glucose in vivo. J Am Chem Soc 126:4534–4535. doi:10.1021/ja0317271
Zhang X, Jantama K, Moore JC, Shanmugan KT, Ingram LO (2007) Production of l-alanine by metabolically engineered Escherichia coli. Appl Microbiol Biotechnol 77:355–366
Zhang KC, Sawaya MR, Eisenberg DS, Liao JC (2008) Expanding metabolism for biosynthesis of nonnatural alcohols. Proc Natl Acad Sci USA 105:20653–20658. doi:10.1073/pnas.0807157106
Zhang K, Li H, Cho KM, Liao JC (2010) Expanding metabolism for total biosynthesis of the nonnatural amino acid l-homoalanine. Proc Natl Acad Sci USA 107:6234–6239. doi:10.1073/pnas.0912903107
Zhou S, Iverson AG, Grayburn WS (2008) Engineering a native homoethanol pathway in Escherichia coli B for ethanol production. Biotechnol Lett 2:335–342. doi:10.1007/s10529-007-9544-x
Zhou J, Zhang H, Zhang Y, Li Y, Ma Y (2012) Designing and creating a modularized synthetic pathway in cyanobacterium Synechocystis enables production of acetone from carbon dioxide. Metab Eng 14:394–400. doi:10.1016/j.ymben.2012.03.005
Acknowledgments
DGW is funded by the KAITEKI Institute. The authors thank Dr. Ryan Marcheschi for critical reading and helpful suggestions.
Conflict of interest
JCL holds financial interest in Easel Biotechnologies, LLC—the company which has licensed this technology from the University of California.
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Wernick, D.G., Liao, J.C. Protein-based biorefining: metabolic engineering for production of chemicals and fuel with regeneration of nitrogen fertilizers. Appl Microbiol Biotechnol 97, 1397–1406 (2013). https://doi.org/10.1007/s00253-012-4605-z
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DOI: https://doi.org/10.1007/s00253-012-4605-z