The metabolism and biotechnological application of betaine in microorganism

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• 作者：Huibin Zou ; Ningning Chen ; Mengxun Shi ; Mo Xian…
• 关键词：Glycine betaine ; Metabolic pathways ; Metabolic engineering ; One ; carbon metabolism ; Methyl group metabolism ; Secondary metabolites
• 刊名：Applied Microbiology and Biotechnology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：100
• 期：9
• 页码：3865-3876
• 全文大小：524 KB
• 参考文献：Annamalai T, Venkitanarayanan K (2009) Role of proP and proU in betaine uptake by Yersinia enterocolitica under cold and osmotic stress conditions. Appl Environ Microbiol 75(6):1471–1477CrossRef PubMed PubMedCentral
  Ashraf M, Foolad MR (2007) Roles of glycine betaine and proline in improving plant abiotic stress resistance. Environ Exp Bot 59(2):206–216CrossRef
  Barra L, Fontenelle C, Ermel G, Trautwetter A, Walker GC, Blanco C (2006) Interrelations between glycine betaine catabolism and methionine biosynthesis in Sinorhizobium meliloti strain 102F34. J Bacteriol 188(20):7195–7204CrossRef PubMed PubMedCentral
  Boncompagni E, Osteras M, Poggi MC, le Rudulier D (1999) Occurrence of choline and glycine betaine uptake and metabolism in the family Rhizobiaceae and their roles in osmoprotection. Appl Environ Microbiol 65(5):2072–2077PubMed PubMedCentral
  Brown AD (1976) Microbial water stress. Bacteriol Rev 40(4):803–846PubMed PubMedCentral
  Cairney J, Booth IR, Higgins CF (1985a) Osmoregulation of gene expression in Salmonella typhimurium: proU encodes an osmotically induced betaine transport system. J Bacteriol 164(3):1224–1232PubMed PubMedCentral
  Cairney J, Booth IR, Higgins CF (1985b) Salmonella typhimurium proP gene encodes a transport system for the osmoprotectant betaine. J Bacteriol 164(3):1218–1223PubMed PubMedCentral
  Chen SY, Lai MC, Lai SJ, Lee YC (2009) Characterization of osmolyte betaine synthesizing sarcosine dimethylglycine N-methyltransferase from Methanohalophilus portucalensis. Arch Microbiol 191(10):735–743CrossRef PubMed
  Choquet G, Jehan N, Pissavin C, Blanco C, Jebbar M (2005) OusB, a broad-specificity ABC-type transporter from Erwinia chrysanthemi, mediates uptake of glycine betaine and choline with a high affinity. Appl Environ Microbiol 71(7):3389–3398CrossRef PubMed PubMedCentral
  Claesen J, Bibb M (2010) Genome mining and genetic analysis of cypemycin biosynthesis reveal an unusual class of posttranslationally modified peptides. Proc Natl Acad Sci 107(37):16297–16302CrossRef PubMed PubMedCentral
  Cluis CP, Burja AM, Martin VJ (2007) Current prospects for the production of coenzyme Q10 in microbes. Trends Biotechnol 25(11):514–521CrossRef PubMed
  Craciun S, Balskus EP (2012) Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci 109(52):21307–21312CrossRef PubMed PubMedCentral
  Craig SA (2004) Betaine in human nutrition. Am J Clin Nutr 80(3):539–549PubMed
  Culham DE, Lasby B, Marangoni AG, Milner JL, Steer BA, van Nues RW, Wood JM (1993) Isolation and sequencing of Escherichia coli gene prop reveals unusual structural features of the osmoregulatory proline betaine transporter, prop. J Mol Bio 229(1):268–276CrossRef
  Diamant S, Rosenthal D, Azem A, Eliahu N, Ben-Zvi AP, Goloubinoff P (2003) Dicarboxylic amino acids and glycine-betaine regulate chaperone-mediated protein-disaggregation under stress. Mol Microbiol 49(2):401–410CrossRef PubMed
  Dickens ML, Ye J, Strohl WR (1995) Analysis of clustered genes encoding both early and late steps in daunomycin biosynthesis by Streptomyces sp. strain C5. J Bacteriol 177(3):536–543PubMed PubMedCentral
  Ding W, Deng W, Tang M, Zhang Q, Tang G, Bi Y, Liu W (2010) Biosynthesis of 3-methoxy-5-methyl naphthoic acid and its incorporation into the antitumor antibiotic azinomycin B. Mol BioSyst 6(6):1071–1081CrossRef PubMed
  Duan XG, Chen J, Wu J (2013) Optimization of pullulanase production in Escherichia coli by regulation of process conditions and supplement with natural osmolytes. Bioresour Technol 146:379–385CrossRef PubMed
  Eklund M, Bauer E, Wamatu J, Mosenthin R (2005) Potential nutritional and physiological functions of betaine in livestock. Nutr Res Rev 18(1):31–48CrossRef PubMed
  Feng J, Wu J, Gao J, Xia Z, Deng Z, He X (2014) Biosynthesis of the beta-methylarginine residue of peptidyl nucleoside arginomycin in Streptomyces arginensis NRRL 15941. Appl Environ Microbiol 80(16):5021–5027CrossRef PubMed PubMedCentral
  Frossard SM, Khan AA, Warrick EC, Gately JM, Hanson AD, Oldham ML, Sanders DA, Csonka LN (2012) Identification of a third osmoprotectant transport system, the osmU system, in Salmonella enterica. J Bacteriol 194(15):3861–3871CrossRef PubMed PubMedCentral
  Galinski EA, Truper HG (1982) Betaine, a compatible solute in the extremely halophilic phototropic bacterium Ectothiorhodospira Halochloris. FEMS Microbiol Lett 13(4):357–360CrossRef
  Galinski EA, Truper HG (1994) Microbial behavior in salt-stressed ecosystems. FEMS Microbiol Rev 15(2–3):95–108CrossRef
  Glaasker E, Heuberger EH, Konings WN, Poolman B (1998) Mechanism of osmotic activation of the quaternary ammonium compound transporter (QacT) of Lactobacillus plantarum. J Bacteriol 180(21):5540–5546PubMed PubMedCentral
  González JC, Peariso K, Penner-Hahn JE, Matthews RG (1996) Cobalamin-independent methionine synthase from Escherichia coli: a zinc metalloenzyme. Biochemistry 35(38):12228–12234CrossRef PubMed
  Gouesbet G, Jebbar M, Talibart R, Bernard T, Blanco C (1994) Pipecolic acid is an osmoprotectant for Escherichia coli taken up by the general osmoporters prou and prop. Microbiol-Uk 140:2415–2422CrossRef
  Gouesbet G, Trautwetter A, Bonnassie S, Wu LF, Blanco C (1996) Characterization of the Erwinia chrysanthemi osmoprotectant transporter gene ousA. J Bacteriol 178(2):447–455PubMed PubMedCentral
  Ikuta S, Imamura S, Misaki H, Horiuti Y (1977) Purification and characterization of choline-oxidase from Arthrobacter globiformis. J Biochem 82(6):1741–1749PubMed
  Kacprzak MM, Lewandowska I, Matthews RG, Paszewski A (2003) Transcriptional regulation of methionine synthase by homocysteine and choline in Aspergillus nidulans. Biochem J 376(Pt 2):517–524CrossRef PubMed PubMedCentral
  Kang SY, Lee JK, Choi O, Kim CY, Jang JH, Hwang BY, Hong YS (2014) Biosynthesis of methylated resveratrol analogs through the construction of an artificial biosynthetic pathway in E. coli. BMC Biotechnol 14:67CrossRef PubMed PubMedCentral
  Kappes RM, Kempf B, Bremer E (1996) Three transport systems for the osmoprotectant glycine betaine operate in Bacillus subtilis: characterization of OpuD. J Bacteriol 178(17):5071–5079PubMed PubMedCentral
  Kato N, Suzuki H, Okumura H, Takahashi S, Osada H (2013) A point mutation in ftmD blocks the fumitremorgin biosynthetic pathway in Aspergillus fumigatus strain Af293. Biosci Biotechnol Biochem 77(5):1061–1067CrossRef PubMed
  Kempf B, Bremer E (1995) OpuA, an osmotically regulated binding protein-dependent transport system for the osmoprotectant glycine betaine in Bacillus subtilis. J Biol Chem 270(28):16701–16713CrossRef PubMed
  Kempf B, Bremer E (1998) Uptake and synthesis of compatible solutes as microbial stress responses to high-osmolality environments. Arch Microbiol 170(5):319–330CrossRef PubMed
  Lai MC, Yang DR, Chuang MJ (1999) Regulatory factors associated with synthesis of the osmolyte glycine betaine in the halophilic methanoarchaeon Methanohalophilus portucalensis. Appl Environ Microbiol 65(2):828–833PubMed PubMedCentral
  Lai MC, Hong TY, Gunsalus RP (2000) Glycine betaine transport in the obligate halophilic archaeon Methanohalophilus portucalensis. J Bacteriol 182(17):5020–5024CrossRef PubMed PubMedCentral
  Lambou K, Pennati A, Valsecchi I, Tada R, Sherman S, Sato H, Beau R, Gadda G, Latge JP (2013) Pathway of glycine betaine biosynthesis in Aspergillus fumigatus. Eukaryot Cell 12(6):853–863CrossRef PubMed PubMedCentral
  Landfald B, Strom AR (1986) Choline-glycine betaine pathway confers a high-level of osmotic tolerance in Escherichia coli. J Bacteriol 165(3):849–855PubMed PubMedCentral
  Lee PT, Hsu AY, Ha HT, Clarke CF (1997) A C-methyltransferase involved in both ubiquinone and menaquinone biosynthesis: isolation and identification of the Escherichia coli ubiE gene. J Bacteriol 179(5):1748–1754PubMed PubMedCentral
  Li KT, Liu DH, Li YL, Chu J, Wang YH, Zhuang YP, Zhang SL (2008) Improved large-scale production of vitamin B12 by Pseudomonas denitrificans with betaine feeding. Bioresour Technol 99(17):8516–8520CrossRef PubMed
  Lidbury I, Murrell JC, Chen Y (2014) Trimethylamine N-oxide metabolism by abundant marine heterotrophic bacteria. Proc Natl Acad Sci 111(7):2710–2715CrossRef PubMed PubMedCentral
  Lu WD, Chi ZM, Su CD (2006) Identification of glycine betaine as compatible solute in Synechococcus sp. WH8102 and characterization of its N-methyltransferase genes involved in betaine synthesis. Arch Microbiol 186(6):495–506CrossRef PubMed
  Luo Y, Lin S, Zhang J, Cooke HA, Bruner SD, Shen B (2008) Regiospecific O-methylation of naphthoic acids catalyzed by NcsB1, an O-methyltransferase involved in the biosynthesis of the enediyne antitumor antibiotic neocarzinostatin. J Biol Chem 283(21):14694–14702CrossRef PubMed PubMedCentral
  Meskys R, Harris RJ, Casaite V, Basran J, Scrutton NS (2001) Organization of the genes involved in dimethylglycine and sarcosine degradation in Arthrobacter spp.: implications for glycine betaine catabolism. Eur J Biochem 268(12):3390–3398CrossRef PubMed
  Millian NS, Garrow TA (1998) Human betaine-homocysteine methyltransferase is a zinc metalloenzyme. Arch Biochem Biophys 356(1):93–98CrossRef PubMed
  Moore SJ, Lawrence AD, Biedendieck R, Deery E, Frank S, Howard MJ, Rigby SE, Warren MJ (2013) Elucidation of the anaerobic pathway for the corrin component of cobalamin (vitamin B12). Proc Natl Acad Sci 110(37):14906–14911CrossRef PubMed PubMedCentral
  Mordukhova EA, Pan JG (2013) Evolved cobalamin-independent methionine synthase (MetE) improves the acetate and thermal tolerance of Escherichia coli. Appl Environ Microbiol 79(24):7905–7915CrossRef PubMed PubMedCentral
  Nakagawa Y, Sota M, Koumoto K (2015) Cryoprotective ability of betaine-type metabolite analogs during freezing denaturation of enzymes. Biotechnol Lett 37(8):1607–1613CrossRef PubMed
  Naughton LM, Blumerman SL, Carlberg M, Boyd EF (2009) Osmoadaptation among vibrio species and unique genomic features and physiological responses of Vibrio parahaemolyticus. Appl Environ Microbiol 75(9):2802–2810CrossRef PubMed PubMedCentral
  Naumann E, Hippe H, Gottschalk G (1983) Betaine: new oxidant in the Stickland reaction and methanogenesis from betaine and L-alanine by a Clostridium sporogenes-Methanosarcina barkeri coculture. Appl Environ Microbiol 45:474–483PubMed PubMedCentral
  Nikel PI, Martinez-Garcia E, de Lorenzo V (2014) Biotechnological domestication of pseudomonads using synthetic biology. Nat Rev Microbiol 12(5):368–379CrossRef PubMed
  Nyyssölä A, Leisola M (2001) Actinopolyspora halophila has two separate pathways for betaine synthesis. Arch Microbiol 176(4):294–300CrossRef PubMed
  Oren A, Elevi Bardavid R, Kandel N, Aizenshtat Z, Jehlicka J (2013) Glycine betaine is the main organic osmotic solute in a stratified microbial community in a hypersaline evaporitic gypsum crust. Extremophiles 17(3):445–451CrossRef PubMed
  Pacholec M, Tao J, Walsh CT (2005) CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis. Biochemistry 44(45):14969–14976CrossRef PubMed
  Park YI, Buszko ML, Gander JE (1999) Glycine betaine: reserve form of choline in Penicillium fellutanum in low-sulfate medium. Appl Environ Microbiol 65(3):1340–1342PubMed PubMedCentral
  Patallo EP, Blanco G, Fischer C, Brana AF, Rohr J, Mendez C, Salas JA (2001) Deoxysugar methylation during biosynthesis of the antitumor polyketide elloramycin by Streptomyces olivaceus. Characterization of three methyltransferase genes. J Biol Chem 276(22):18765–18774CrossRef PubMed
  Peter H, Burkovski A, Kramer R (1998) Osmo-sensing by N- and C-terminal extensions of the glycine betaine uptake system BetP of Corynebacterium glutamicum. J Biol Chem 273(5):2567–2574CrossRef PubMed
  Proctor LM, Lai R, Gunsalus RP (1997) The methanogenic archaeon Methanosarcina thermophila TM-1 possesses a high-affinity glycine betaine transporter involved in osmotic adaptation. Appl Environ Microbiol 63(6):2252–2257PubMed PubMedCentral
  Riekhof WR, Sears BB, Benning C (2005) Annotation of genes involved in glycerolipid biosynthesis in Chlamydomonas reinhardtii: discovery of the betaine lipid synthase BTA1Cr. Eukaryot Cell 4(2):242–252CrossRef PubMed PubMedCentral
  Robert H, Le Marrec C, Blanco C, Jebbar M (2000) Glycine betaine, carnitine, and choline enhance salinity tolerance and prevent the accumulation of sodium to a level inhibiting growth of Tetragenococcus halophila. Appl Environ Microbiol 66(2):509–517CrossRef PubMed PubMedCentral
  Roeûler M, Mûller K (2001) Osmoadaptation in bacteria and archaea: common principles and differences. Environ Microbiol 3(12):743–754CrossRef
  Rönsch H, Kramer R, Morbach S (2003) Impact of osmotic stress on volume regulation, cytoplasmic solute composition and lysine production in Corynebacterium glutamicum MH20-22B. J Biotechnol 104(1–3):87–97CrossRef PubMed
  Sakamoto A, Hayashi H, Tony A, Chen HH, Murata N (2000) Genetic engineering of biosynthesis of glycine betaine enhances tolerance to various stress. In: Cherry JH, Locy RD, Rychter A (ed) Plant tolerance to abiotic stresses in agriculture: role of genetic engineering. Kluwer Academic Publishers, pp 95–104
  Sarkar M, Pielak GJ (2014) An osmolyte mitigates the destabilizing effect of protein crowding. Protein Sci 23(9):1161–1164CrossRef PubMed PubMedCentral
  Schiefner A, Holtmann G, Diederichs K, Welte W, Bremer E (2004) Structural basis for the binding of compatible solutes by ProX from the hyperthermophilic archaeon Archaeoglobus fulgidus. J Biol Chem 279(46):48270–48281CrossRef PubMed
  Scholz R, Molohon KJ, Nachtigall J, Vater J, Markley AL, Sussmuth RD, Mitchell DA, Borriss R (2011) Plantazolicin, a novel microcin B17/streptolysin S-like natural product from Bacillus amyloliquefaciens FZB42. J Bacteriol 193(1):215–224CrossRef PubMed PubMedCentral
  Selmer-Olsen E, Sorhaug T, Birkeland SE, Pehrson R (1999) Survival of Lactobacillus helveticus entrapped in Ca-alginate in relation to water content, storage and rehydration. J Ind Microbiol Biotechnol 23(2):79–85CrossRef PubMed
  Serra AL, Mariscotti JF, Barra JL, Lucchesi GI, Domenech CE, Lisa AT (2002) Glycine betaine transmethylase mutant of Pseudomonas aeruginosa. J Bacteriol 184(15):4301–4303CrossRef PubMed PubMedCentral
  Shintani D, DellaPenna D (1998) Elevating the vitamin E content of plants through metabolic engineering. Science 282(5396):2098–2100CrossRef PubMed
  Shintani DK, Cheng Z, DellaPenna D (2002) The role of 2-methyl-6-phytylbenzoquinone methyltransferase in determining tocopherol composition in Synechocystis sp. PCC6803. FEBS Lett 511:1–5CrossRef PubMed
  Smith LT, Pocard JA, Bernard T, Le Rudulier D (1988) Osmotic control of glycine betaine biosynthesis and degradation in Rhizobium meliloti. J Bacteriol 170(7):3142–3149PubMed PubMedCentral
  Steffensky M, Muhlenweg A, Wang ZX, Li SM, Heide L (2000) Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891. Antimicrob Agents Chemother 44(5):1214–1222CrossRef PubMed PubMedCentral
  Suzuki H, Tamamura R, Yajima S, Kanno M, Suguro M (2005) Corynebacterium sp. U-96 contains a cluster of genes of enzymes for the catabolism of sarcosine to pyruvate. Biosci Biotechnol Biochem 69(5):952–956CrossRef PubMed
  Tang MC, Fu CY, Tang GL (2012) Characterization of SfmD as a heme peroxidase that catalyzes the regioselective hydroxylation of 3-methyltyrosine to 3-hydroxy-5-methyltyrosine in saframycin A biosynthesis. J Biol Chem 287(7):5112–5121CrossRef PubMed PubMedCentral
  Ticak T, Kountz DJ, Girosky KE, Krzycki JA, Ferguson DJ (2014) A nonpyrrolysine member of the widely distributed trimethylamine methyltransferase family is a glycine betaine methyltransferase. Proc Natl Acad Sci 111(43):E4668–E4676CrossRef PubMed PubMedCentral
  Ticak T, Hariraju D, Arcelay MB, Arivett BA, Fiester SE, Ferguson DJ (2015) Isolation and characterization of a tetramethylammonium-degrading Methanococcoides strain and a novel glycine betaine-utilizing methanolobus strain. Arch Microbiol 197:197–209CrossRef PubMed
  Underwood SA, Buszko AL, Shanmugam KT, Ingram LO (2004) Lack of protective osmolytes limits final cell density and volumetric productivity of ethanologenic Escherichia coli KO11 during xylose fermentation. Appl Environ Microbiol 70(5):2734–2740CrossRef PubMed PubMedCentral
  Vanhauteghem D, Janssens GP, Lauwaerts A, Sys S, Boyen F, Cox E, Meyer E (2013) Exposure to the proton scavenger glycine under alkaline conditions induces Escherichia coli viability loss. PLoS one 8(3):e60328CrossRef PubMed PubMedCentral
  Waditee R, Tanaka Y, Aoki K, Hibino T, Jikuya H, Takano J, Takabe T, Takabe T (2003) Isolation and functional characterization of N-methyltransferases that catalyze betaine synthesis from glycine in a halotolerant photosynthetic organism Aphanothece halophytica. J Biol Chem 278(7):4932–4942CrossRef PubMed
  Wang ZX, Li SM, Heide L (2000) Identification of the coumermycin A(1) biosynthetic gene cluster of Streptomyces rishiriensis DSM 40489. Antimicrob Agents Chemother 44(11):3040–3048CrossRef PubMed PubMedCentral
  Wargo MJ (2013) Homeostasis and catabolism of choline and glycine betaine: lessons from Pseudomonas aeruginosa. Appl Environ Microbiol 79(7):2112–2120CrossRef PubMed PubMedCentral
  Watkins AJ, Roussel EG, Parkes RJ, Sass H (2014) Glycine betaine as a direct substrate for methanogens (Methanococcoides spp.). Appl Environ Microbiol 80(1):289–293CrossRef PubMed PubMedCentral
  Xu K, Xu P (2014a) Betaine and beet molasses enhance L-lactic acid production by Bacillus coagulans. PLoS one 9(6):e100731CrossRef PubMed PubMedCentral
  Xu J, Xia X, Zhang J, Guo Y, Zhang W (2014b) An overlooked effect of glycine betaine on fermentation: prevents caramelization and increases the L-lysine production. J Microbiol Biotechnol 24(10):1368–1376CrossRef PubMed
  Yakimov MM, La Cono V, Slepak VZ, La Spada G, Arcadi E, Messina E, Borghini M, Monticelli LS, Rojo D, Barbas C, Golyshina OV, Ferrer M, Golyshin PN, Giuliano L (2013) Microbial life in the Lake Medee, the largest deep-sea salt-saturated formation. Sci Rep 3:3554CrossRef PubMed PubMedCentral
  Zhang Q, van der Donk WA (2012) Catalytic promiscuity of a bacterial alpha-N-methyltransferase. FEBS Lett 586(19):3391–3397CrossRef PubMed PubMedCentral
  Zhang J, Cao T, Tang Z, Shen Q, Rosen BP, Zhao FJ (2015) Arsenic methylation and volatilization by arsenite S-adenosylmethionine methyltransferase in Pseudomonas alcaligenes NBRC14159. Appl Environ Microbiol 81(8):2852–2860CrossRef PubMed PubMedCentral
  Zhou S, Grabar TB, Shanmugam KT, Ingram LO (2006) Betaine tripled the volumetric productivity of D(−)-lactate by Escherichia coli strain SZ132 in mineral salts medium. Biotechnol Lett 28(9):671–676CrossRef PubMed
  Zhu Y, Eiteman MA, Altman R, Altman E (2008) High glycolytic flux improves pyruvate production by a metabolically engineered Escherichia coli strain. Appl Environ Microbiol 74(21):6649–6655CrossRef PubMed PubMedCentral
  Zou H, Wu Z, Xian M, Liu H, Cheng T, Cao Y (2013) Not only osmoprotectant: betaine increased lactate dehydrogenase activity and L-lactate production in lactobacilli. Bioresour Technol 148:591–595CrossRef PubMed
  
• 作者单位：Huibin Zou (1) (2)
  Ningning Chen (1)
  Mengxun Shi (1)
  Mo Xian (2)
  Yimin Song (1)
  Junhong Liu (1)
  
  1. College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China
  2. CAS Key Laboratory of Bio-based Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Biotechnology
  Microbiology
  Microbial Genetics and Genomics
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0614

文摘

Glycine betaine (betaine) is widely distributed in nature and can be found in many microorganisms, including bacteria, archaea, and fungi. Due to its particular functions, many microorganisms utilize betaine as a functional chemical and have evolved different metabolic pathways for the biosynthesis and catabolism of betaine. As in animals and plants, the principle role of betaine is to protect microbial cells against drought, osmotic stress, and temperature stress. In addition, the role of betaine in methyl group metabolism has been observed in a variety of microorganisms. Recent studies have shown that betaine supplementation can improve the performance of microbial strains used for the fermentation of lactate, ethanol, lysine, pyruvate, and vitamin B₁₂, during which betaine can act as stress protectant or methyl donor for the biosynthesis of structurally complex compounds. In this review, we summarize the transport, synthesis, catabolism, and functions of betaine in microorganisms and discuss potential engineering strategies that employ betaine as a methyl donor for the biosynthesis of complex secondary metabolites such as a variety of vitamins, coenzymes, and antibiotics. In conclusion, the biocompatibility, C/N ratio, abundance, and comprehensive metabolic information of betaine collectively indicate that this molecule has great potential for broad applications in microbial biotechnology.