Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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The Actinobacterium Corynebacterium glutamicum, an Industrial Workhorse

  • Lee, Joo-Young (Department of Biotechnology, The Catholic University of Korea) ;
  • Na, Yoon-Ah (Department of Biotechnology, The Catholic University of Korea) ;
  • Kim, Eungsoo (Department of Biological Engineering, Inha University) ;
  • Lee, Heung-Shick (Department of Biotechnology and Bioinformatics, Korea University) ;
  • Kim, Pil (Department of Biotechnology, The Catholic University of Korea)
  • Received : 2016.01.21
  • Accepted : 2016.01.31
  • Published : 2016.05.28
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Abstract

Starting as a glutamate producer, Corynebacterium glutamicum has played a variety of roles in the industrial production of amino acids, one of the most important areas of white biotechnology. From shortly after its genome information became available, C. glutamicum has been applied in various production processes for value-added chemicals, fuels, and polymers, as a key organism in industrial biotechnology alongside the surprising progress in systems biology and metabolic engineering. In addition, recent studies have suggested another potential for C. glutamicum as a synthetic biology platform chassis that could move the new era of industrial microbial biotechnology beyond the classical field. Here, we review the recent progress and perspectives in relation to C. glutamicum, which demonstrate it as one of the most promising and valuable workhorses in the field of industrial biotechnology.

Keywords

Introduction

Corynebacterium glutamicum was isolated in the search to identify a natural glutamate producer by researchers of the company Kyowa Hakko in 1956 [70]. C. glutamicum is a gram-positive, non-endotoxin, non-sporulating, and generally recognized as safe (GRAS) host that has been widely used for the industrial production of ʟ-glutamate and ʟ-lysine. The publication of the C. glutamicum ATCC 13032 genome sequence by two independent groups [43,50] in 2003 could be regarded as the beginning of a new era for C. glutamicum in the field of industrial microbiology and biotechnology. The release of the complete genome sequence provided a platform that would allow better understanding and easier engineering of C. glutamicum. Heretofore, the progress in metabolic engineering based on the development and integration of genetic engineering tools, systems biology, and omics-based global analysis techniques brought C. glutamicum forward from among the many other workhorses used in industry [10,149]. During the last decade, more than 100 studies reporting on the development and application of high-throughput technologies such as genomics, transcriptomics, proteomics, and metabolomics have been published. The annual number of both publications and patents increased quickly after the complete genome information was released (Fig. 1A). First, transcriptome analysis using DNA microarray was established in the early 2000s [35,84,89,147]. Later, approaches followed for the analysis of global transcriptional regulatory networks in C. glutamicum [8,124,149], the analysis of industrial producer strains [19,35,67,74,128], and the analysis of fermentation processes [15,55]. In addition to the application of high-throughput sequencing in transcriptome analysis, the development of RNA-seq [107] as an alternative to DNA microarray and capillary DNA sequencing allowed faster, deeper, and more precise insights into understanding the transcriptional regulatory mechanisms [92], function, and occurrence of small RNAs [87]. RNA-seq has also been applied in the analysis of adaptive evolution [78] and lysine producer strains [64]. The development and application of proteomics analysis tools such as 2-D PAGE for high-throughput, high-resolution proteome separation and MALDI-TOF MS provided a proteome reference map with comprehensive coverage of proteins [12,37,115]. Here, we summarize the studies and achievements relating to C. glutamicum, including recent progress in the field of bio-based production of value-added chemicals and recombinant proteins. Selected cases of achievements relating to C. glutamicum are provided in this mini-review.

Fig. 1.A brief history of Corynebacterium glutamicum. (A) The annual number of reports relevant to C. glutamicum. (B) Historical and technical milestones in C. glutamicum (upper), together with milestones in biotechnology (lower). Boxes: technical and historical events in biotechnology (gray); fermentation or metabolic engineering in microbes (black); trends in microbial biotechnology (gray-filled). Remarkable historical events are highlighted in bold.

 

Timeline of C. glutamicum as an Industrial Microbe

After isolation as a glutamate producer, much effort was made to understand C. glutamicum as well as to develop this microbe for industrial purposes. Up to 2015, over 2,700 papers and 1,700 patents have been reported relating to C. glutamicum. Among those reports, we selected and summarized the annual number of the reports in Fig. 1A and historical and technical milestones in Fig. 1B.

History of C. glutamicum Strains (Isolation, Engineering, and Future)

In the 1950s, Abe and colleagues at Kyowa Hakko carried out taxonomical studies on 208 glutamate-producing strains, isolating what was designated as Micrococcus glutamicum, but which later came to be known as C. glutamicum [1,70]. These strains and numerous other strains were assorted to the genera Brevibacterium, Microbacterium, Micrococcus, or Arthrobacter. Later, owing to progress in taxonomy (e.g., 16S rDNA sequence analysis and FT-IR spectral comparison), many of the formerly mis-classified strains were reclassified as C. glutamicum [80,93]. Among the first-isolated strains, ATCC13032, a wild-type strain of C. glutamicum, was mostly studied for examination of its physiological properties, metabolism, development of genetic tools, and engineering of C. glutamicum. Another widely used type strain, C. glutamicum R, was first applied for cultivation under conditions of oxygen deprivation. The R strain was then engineered in order to produce ethanol and organic acids such as succinate, lactate, and acetate, using its anaerobic metabolism under oxygen-deprived conditions. Meanwhile, many industrial C. glutamicum strains (screened or engineered) were also studied. To date, 227 type strains, including ATCC13032, have been deposited at American Type Culture Collection (ATCC; http://www.actt.org). In addition, 50 type strains can be found at StrainInfo (http:// www.straininfo.net/taxa/569). Recently, AR strains that were mutated and metabolically engineered to enhance the production of arginine [103], genome-reduced strains initiated from prophage-free strain MB001 [7,138], and a minicells-generating strain that can be applied in drug delivery systems [77] have been reported. Genome information of the first-published complete genome sequence of C. glutamicum has been made available at CoryneRegNet (http://www.coryneregnet.de) and KEGG (http://www.kegg.jp).

To date, genome assembly and annotation reports of 14 strains (9 complete genomes; 5 draft genomes) can be found in the genome database at NCBI (http://www.ncbi.nlm.nih.gov/genome/genomes/469). Reported genome assembly and annotation in NCBI are shown in Table 1. The small cryptic plasmids such as pBL1 and pAG3 were also found in C. glutamicum and other coryneform bacteria (Table 2).

Table 1.a Symbols: ●, complete genome sequence; ◐, draft genome sequence (scaffold or contig).

Table 2.Native plasmids of C. glutamicum registered in NCBI.

Benefits of C. glutamicum as an Industrial Host

C. glutamicum has many fundamental physiological properties that make it an important industrial workhorse. These properties are listed as follows: (i) GRAS, generally C. glutamicum is recognized as a safe strain for human; (ii) fast growth to high cell densities [32]; (iii) genetically stable owing to the lack of a recombination repair system [90]; (iv) limited restriction-modification system [143]; (v) no autolysis and maintenance of metabolic activity under growth-arrested conditions [44]; (vi) low protease activity favoring recombinant protein production [59]; (vii) plasticity of metabolism and strong secondary metabolism properties [148]; and (viii) broad spectrum of carbon utilization (pentoses, hexoses, and alternative carbon sources); stress-tolerance to carbon sources [59,113]. Taken together, these physiological properties render C. glutamicum accessible to manipulation and cultivation in robust industrial conditions.

Toolbox

Numerous physiological and genetic techniques were developed to understand and manipulate C. glutamicum after genome sequences of several strains were made available [43,50,157], and genetic engineering tools have also been developed that are now available to be used in the manipulation of C. glutamicum. Historical events of toolbox development for C. glutamicum are briefly shown in Fig. 1B.

Genome manipulations. Owing to advancements in recombinant DNA technology, various tools for genome manipulation of C. glutamicum have been developed since the 1990s [36,40,120,139]. Basic tools, such as gene integration, replacement, and disruption for genome engineering of C. glutamicum were developed and established from a conjugation system of E. coli using mobilizable (mob-carrying) vectors [120]. Attempts were made to enhance the transfer efficiency and overcome the restriction-modification system (e.g., dam-, dcm-, mcrBC- mutants) [114]. Single-crossover recombination [143] and double-crossover recombination (markerless method) were developed for gene replacement or disruption methods via events [114]. Cre/loxP-mediated recombination systems to rearrange large genome regions have been reported [129-132]. Recently, Unthan et al. [138] reported that combinatory deletions of irrelevant large genes would decrease the genome size to 2,561 kbp.

Promoters and plasmids. In addition to the research on the screening of native promoters of C. glutamicum, there has been development of promoters using mutation and selection for engineering purposes, particularly in strong and constitutive promoters (e.g., Pfbp, Psod, and Ptuf) [99]. Most inducible promoters and vectors were adopted from the inducible expression systems of E. coli promoters (e.g., Plac, Ptac, and Ptrc) and lac operator-repressor. Even leaderless fully synthetic promoters have been recently reported [153]. Promoters used in engineering of C. glutamicum are summarized in Table 3. Attempts to tightly regulate protein expression induction by IPTG have been made numerous times using different vectors such as pEKEx1, pXMJ19, and pVWEx1 [27,45,105]. Owing to the low IPTG permeability of C. glutamicum, IPTG inducible expression systems tend to display a lower level of expression in C. glutamicum than those in E. coli [104]. However, a recent study reported that an engineered C. glutamicum carrying the DE3 region from E. coli BL21 (DE3) showed tight regulation as well as controllable expression using IPTG with a homogenous population [72].

Table 3.Summary of promoters used in engineering of C. glutamicum.

After small native plasmids were discovered in amino acid-producing corynebacteria in the 1980s (Table 2), plasmid vectors were developed [57,112]. Based on native plasmids, vectors for various purposes (cloning, promoter activity report, and expression) were developed starting from the 1990s [27,36,41,120,139,140]. Plasmid vectors used in the engineering of C. glutamicum are summarized in Table 4. Recent progress in synthetic biology (e.g., commercial gene synthesis, biobrick parts) can make combinatorial assembly of various constructions possible with less effort than before.

Table 4.aTc, anhydrotetracycline; Cm, chloramphenicol; IPTG, isopropyl β-D-1-thiogalactopyranoside ; Km, kanamycin.

 

Bio-Based Chemicals from C. glutamicum

C. glutamicum has had excellent success in the large-scale production of glutamate and lysine accompanied by an increase in knowledge of the metabolism and regulatory networks as well as the development of tools for genetic engineering. As such, C. glutamicum has become the preferred microbe in white biotechnology for the industrial production of value-added chemicals. A summary of the current status of the production of bio-based chemicals with C. glutamicum is shown in Table 5.

Table 5.n.d., not determined. Numerical values in titer, yield, and productivity were adapted or calculated based on values in the references. aMaximum conversion yield.

Amino Acids

Starting with ʟ-glutamate and ʟ-lysine, C. glutamicum was applied to industrial production of various amino acids during the half century after its discovery in the 1950s (Fig. 1B). Amino acids have various characteristics in terms of chemical properties, taste, and nutritional value, and thus have many potential uses, such as feed supplements, food additives, and materials for pharmaceuticals and polymers. Most ʟ-amino acids are produced by microbial fermentation. Within a few years after the first report of ʟ-glutamate fermentation with C. glutamicum [70], the microbe was also used to produce ʟ-lysine (Fig. 1B, [91]). In the early era, strain development for amino acid fermentation depended on random mutation and selection such as analog-resistant mutant screening, which contributed to the development of many commercial and potent producers [39]. Along with the advancement in genetic engineering technology, development and application of DNA technology to C. glutamicum for amino acid production began in the 1980s. From the beginning until the present day, the amino acid ʟ-glutamate has possessed the largest market share of amino acid fermentation (2.5 M tons/year), relying on C. glutamicum for its production. Recently, Zhang et al. [161] reported on a ʟ-glutamate-producing C. glutamicum with the highest titer and productivity of 120 g/l and 5 g/l·h, respectively. The amino acid ʟ-lysine represents the second largest share of the market (1.5 M tons/year). Becker et al. [11] reported on an efficient ʟ-lysine hyper-producer with a titer of 120 g/l, productivity of 4.0 g/l·h, and a yield of 0.55 g/g-carbon developed through synthetic metabolic engineering of C. glutamicum. In the 2000s, production expanded to other amino acids such as ʟ-arginine, ʟ- alanine, and ʟ-methionine, and further to derived valuable chemicals such as γ-aminobutyrate (GABA), which can be applied in functional foods, pharmaceuticals, or polyamide.

Alcohols and Organic Acids

Owing to its leading role as an amino acid producer, studies on C. glutamicum have focused on amino acid biosynthetic pathways. However, fermentation of alcohols such as ethanol and isobutanol under oxygen-deprived conditions has been reported [16,44,49,125,151]. Furthermore, efforts to produce organic acids such as succinate, lactate, 2-ketoglutarate, and 2-ketoisovalerate have proven that C. glutamicum can also produce valuable organic acids. The possibilities for the use of C. glutamicum in industrial applications have also been investigated. For example, there have been reports of ethanol (119 g/l), isobutanol (73 g/l), ʟ-lactate (95.6 g/l), D-lactate (120 g/l), and succinate (156 g/l) production under conditions of oxygen deprivation [16,44,49,125,151].

Polymers

There have been efforts made to produce polymers such as diamines (putrescine, cadavarine) and polyhydroxybutyrate (PHB) with engineered C. glutamicum; for example, recombinant ornithine-producing C. glutamicum has been used to produce diamine 1,4-diaminobutane (putrescine) and 1,5-diaminopentane (cadaverine) derived from ʟ-ornithine by decarboxylation [19,69,117-119]. Recombinant C. glutamicum expressing PhbCAB from Ralstonia eutropha accumulated up to 6.0 g/l polyhydroxyalkanoate (PHA) and 0.99 g/l PHB, respectively [83,86].

 

Heterologous Protein Expression in C. glutamicum

As mentioned above, C. glutamicum has been widely used as an industrial workhorse for the production of amino acids and various bio-based chemicals. Moreover, an increasing number of reports indicate C. glutamicum to have great potential as a platform microbe for heterologous protein expression (Table 6). Owing to the many intrinsic attributes of C. glutamicum, a broad range of different approaches has been used to investigate its potential as a host for the expression of heterologous proteins. There are several successful examples showing that heterologous expression in C. glutamicum enhanced the production of amino acids and other value-added chemicals, or allowed the utilization of various carbon sources via metabolic engineering approaches.

Table 6.Summary of the heterologous expression cases in C. glutamicum.

Table 6.n.q., not quantified. aMaximum conversion yield.

Intrinsic Advantages of C. glutamicum as a Protein Expression Host

C. glutamicum has intrinsic advantages as a microbial cell factory for protein production. A low level of extracellular protease activity and the presence of two native protein secretion mechanisms, the general secretory (Sec-dependent) pathway and the twin-arginine translocation (TAT-dependent) pathway have been known to enhance the secretion of homologous and heterologous proteins. Proteome analyses of C. glutamicum showed that approximately 10% of the proteins coded by wild-type C. glutamicum could be secreted [51]. Many species belonging to Corynebacterium are known to possess low protease activity unlike many other soil bacteria such as those of the Streptomyces and Bacillus genera. It has been identified that C. glutamicum has only one extracellular protease coding gene in its genome, the extracellular trypsin-like protease gene etpr (cg1243, cgR1176) [157]. To date, two well-identified independent secretion pathways have been utilized to enhance the secretion of proteins in C. glutamicum: the Sec-dependent and TAT-dependent pathways. Overexpression of components of the Sec and the TAT pathways, such as Sec(E/Y)DF and TatABC, has been suggested as a method to reduce molecular bottlenecks [63]. Moreover, the signal peptides type I and II have also been investigated to enhance secretion efficiency, such as signal sequences 29, 11, and 8 for Sec, Tat (type I), and lipoprotein (type II), respectively [142].

Heterologous Protein Expression

As shown in Table 6, heterologous expression in C. glutamicum has been reported. Amylases from other soil bacteria such as Bacillus amyloliquefaciens, Geobacillus stearothermophilus, Streptomyces bovis, and Streptomyces griseus were successfully expressed in various C. glutamicum strains [20,126,133,146,154]. Numerous cases have shown that heterologous expression enhanced the production of natural or non-natural compounds in C. glutamicum; for example, Pseudomonas taetrolens ArgR enabled the production of D-amino acids in an engineered C. glutamicum strain [127]. More recently, a synthetic Pseudomonas stutzeri ectoine gene cluster enabled the production of ectoine, a chemical chaperone that has a stabilizing effect on biological molecules in C. glutamicum [9].

 

Concluding Remarks and Outlook

Best known for its use over a period of decades in industry as a glutamate and lysine producer, C. glutamicum has been widely used in various applications and is considered as one of the most preferred microbes used for metabolic engineering. A number of approaches for enhancing secretion efficiency have been identified, such as the use of signal peptides. However, C. glutamicum has some disadvantages when compared with E. coli, such as a much lower transformation efficiency and a low number of available expression systems. To overcome these issues, a remarkable effort should be made to develop expression systems and secretion machinery.

Taken together, we still need to develop the toolbox that will allow us to gain a deeper understanding and increase production speed. However, we can surely expect further progress for C. glutamicum as a microbial value-adding producer workhorse in the field of microbial biotechnology.

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