Heme and menaquinone induced electron transport in lactic acid bacteria
© Brooijmans et al; licensee BioMed Central Ltd. 2009
Received: 18 February 2009
Accepted: 29 May 2009
Published: 29 May 2009
For some lactic acid bacteria higher biomass production as a result of aerobic respiration has been reported upon supplementation with heme and menaquinone. In this report, we have studied a large number of species among lactic acid bacteria for the existence of this trait.
Heme- (and menaquinone) stimulated aerobic growth was observed for several species and genera of lactic acid bacteria. These include Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacilllus brevis, Lactobacillus paralimentarius, Streptococcus entericus and Lactococcus garviae. The increased biomass production without further acidification, which are respiration associated traits, are suitable for high-throughput screening as demonstrated by the screening of 8000 Lactococcus lactis insertion mutants. Respiration-negative insertion-mutants were found with noxA, bd-type cytochrome and menaquinol biosynthesis gene-disruptions. Phenotypic screening and in silico genome analysis suggest that respiration can be considered characteristic for certain species.
We propose that the cyd-genes were present in the common ancestor of lactic acid bacteria, and that multiple gene-loss events best explains the observed distribution of these genes among the species.
Lactic acid bacteria are extensively used for the production of a diverse range of fermented foods with improved shelf-life, taste and nutritional properties [1–3]. The consumption of certain strains of lactic acid bacteria, called probiotics, may even provide health benefits by preventing or reducing disease symptoms [4, 5]. Lactic acid bacteria are typically cultivated in (micro)anaerobic food-environments and have been (historically) classified as non-respiring, facultative anaerobes.
Since the early seventies, however, observations were made that heme could induce behavior that resembles respiration in several lactic acid bacteria that included Lactococcus lactis, Enterococcus faecalis, Streptococcus species and Leuconostoc mesenteriodes. Heme stimulated the aerobic growth of these species and/or induced cytochrome formation [6–9]. Recent experimental work provided conclusive evidence for actual respiration in Lactococcus lactis. Typically, respiratory chains consist of dehydrogenases, a membrane integral electron shuttle, such as quinones, and cytochromes and can generate a proton motive force. Menaquinone production by Lactococcus lactis strains has been observed, as well as, genes found that encode menaquinone biosynthesis in the sequenced genomes [10–12]. Moreover, the Lactococcus lactis respiratory chain contains a heme-dependent bd-type cytochrome, encoded by the cydABCD operon that is capable of generating a proton motive force [13, 14].
Heme-induced respiration dramatically alters the phenotype of Lactococcus lactis, as it not only improves growth-efficiency but also robustness (improved stress resistance) [15, 16]. The industrial relevance of these respiration-associated traits are made apparent by existing industrial and patent applications, for improved production of starter cultures [17, 18].
Over the years several additional lactic acid bacteria were identified with a similar response to heme as Lactococcus lactis. A more structured investigation of the distribution of this trait among lactic acid bacteria, however, has not been conducted [19, 20]. In this study, we aim to find more species of lactic acid bacteria that are potential respirators. As it also remains unclear whether respiration can be considered a species-specific trait, for a number of species multiple strains are examined. Furthermore, with the availability of numerous sequenced genomes, we can use in silico data as well to find potential respirators among the lactic acid bacteria.
Bacterial strains and growth conditions
Lactic acid bacterial species and strains used in this study.
Lactic acid bacteria used in this study
Lactobacillus delbrueckii delbrueckii
Lactobacillus gasseri VP
Enterococcus mundii collins
Lactobacillus sakei sakei
Lactobacillus coryniformis torguens
Aerobic growth conditions were achieved in shake flask cultivations with a 1:10 medium/volume ratio, while shaking at 250 rpm. For high throughput (96-wells micro-titer plates) aerobic cultivations, microtiter plates were filled with 150 μl medium/well (well volume μl 320), covered with breathseals and incubated in a microtron, shaking at 1000 rpm (Greiner Bio-one, Germany). The conditions of cultures grown in stationary tubes were considered anaerobic (or micro-aerobic). All strains were grown for 48 hours at 30°C before measuring biomass (optical density at 600 nm) and acidification.
Measurement of menaquinone-content of bacterial cells
The following standard method was used for menaquinone measurement in cells; Overnight cultures were washed twice in phosphate buffer (50 mM K2HPO4, pH 5.0) and re-suspended to an OD600 of 10. Of this cell-suspension 2 ml was lysed by bead beating, using 0.1 mm silica-beads (Biospec products, Inc) in a Savant Bio 101 FastPrep FP120 and frozen till further use. Menaquinones were extracted by thoroughly mixing 500 μl of this lysed cell-suspension with 5 ml extraction buffer (90%hexane, 10% ethanol). The hexane layer was transferred to a new tube after centrifugation. This extraction procedure was repeated twice, and the combined hexane layers subsequently evaporated under nitrogen-gas. The precipitated menaquinones were re-dissolved in 300 μl ethanol. This menaquinone solution was analysed on a Thermo Finnigan (Waltham, MA) TSQ Quantum ms-ms system in combination with a Shimadzu (Kyoto, Japan) LC system. The samples were injected on a Synergi 4μ MAX-RP 80A 150 × 2 mm (Phenomenex) column where the compounds were eluted with a linear gradient, starting with 100% water/methanol 25/75 to 100% 2-propanol and detected with ms-ms. The TSQ Quantum ms system was equipped with an APCI (Atmospheric Pressure Chemical Ionization) source, set in the negative mode. A capillary temperature of 210°C was used with a vaporizer temperature of 300°C and a sheat gas pressure of 21psi. The collision energy for measuring in ms2 was set at 38 Volt for all compounds.
Analysis of genomic content of sequenced lactic acid bacteria
The presence of the cydABCD and the menaquinone biosynthesis genes were based on annotation of the respective complete genome sequences and by homology analysis with Lactococcus lactis MG1363 gene-products, using BLASTP 2.2.18 (basic local alignment search tool) [12, 22]. Comparison of genomic local organization was performed using the KEGG genome map http://www.kegg.com/, and the pinned region function of ERGO http://ergo.integratedgenomics.com/ERGO/.
DNA handling techniques
The identification of the genomic site of integration of the transposase gene, of the selected respiratory-defective, Lactococcus lactis B1157 mutants, was performed as described previously .
Phylogenetic analysis of the cyd-genes
Each individual cydABCD gene product of Lactococcus lactis MG1363 was entered as a query to search for homologues in other lactic acid bacteria using the BLAST algorithm . Sequence entries found to be homologous were retrieved (june '08) from GenBank, and separately aligned using the MUSCLE algorithm . From the amino acid sequence alignments, bootstrapped neighbor joining trees were obtained using Clustal  with default settings, except for the number of iterations, which was set to 1000. Trees were analyzed in LOFT  and visualized in MEGA3 . An identical exercise was carried out for 16S rRNA sequences from the organisms that were found to contain cyd-genes. Finally, the topology of the four trees, based on the cyd-gene products, was analyzed and compared to a standard phylogeny tree based on 16S rRNA.
Screening for respiration in lactic acid bacteria
Heme-stimulated growth of lactic acid bacteria
Carnobacterium divergens 1
Heme and menaquinone-stimulated growth of lactic acid bacteria.
Lactobacillus paralimentarius 1
Streptococcus entericus 1
Streptococcus agalactiae 2
Menaquinones form a part of electron transport chains, facilitating membranous electron transfer . Many lactic acid bacteria are unable to produce menaquinones (more widely known as vitamin K2). Addition of both heme and menaquinone to aerated cultures of Lactobacillus plantarum WCFS1 increased the final (stationary phase) biomass and pH, quite similar to the heme supplemented phenotype of Lactococcus lactis (Fig 1 and Table 3). This is in agreement with the absence of a complete gene-set, in Lactobacillus plantarum, for menaquinone biosynthesis http://www.kegg.com. The measured biomass (OD600) levels of Lactobacillus plantarum, grown with or without heme and menaquinone, remained relatively stable after the onset of the stationary phase (data not shown). In our selection of lactic acid bacteria we observed that Lactococcus garviae, Lactobacillus rhamnosus, Lactobacillus brevis and Enterococcus faecalis also require both heme and menaquinone for aerobic growth stimulation (Table 3). As reported in literature, a combination of these cofactors also stimulate biomass formation in Streptococcus agalactiae NEM316 . Furthermore, heme-induced cytochrome formation in Leuconostoc mesenteriodes (NCIB 9917) and Enterococcus faecalis (V538) has also been reported [6, 19, 29, 30].
Distribution of cyd-genes in lactic acid bacteria
The presence of cytochrome genes in the sequenced lactic acid bacteria.
locus annotated as bd- cytochrome genes or with BLAST similarity%a:
structural subunits I & II
associated ABC transporter
Enterococcus faecalis V583
Lactobacillus brevis ATCC 367
Lactobacillus casei ATCC 334
Lactobacillus gasseri ATCC 33323
Lactobacillus johnsonii NCC 533
Lactobacillus plantarum WCFS1
Lactobacillus reuteri 100-23
Lactobacillus reuteri F275
Lactobacillus salivarius UCC118
Lactococcus lactis MG1363
Lactococcus lactis SK11
Lactococcus lactis Il1403
Leuconostoc mesenteroides ATCC 8293
Oenococcus oeni ATCC BAA-1163
Oenococcus oeni PSU-1
Streptococcus agalactiae 18RS21
Streptococcus agalactiae 2603V/R
Streptococcus agalactiae 515
Streptococcus agalactiae A909
Streptococcus agalactiae CJB111
Streptococcus agalactiae COH1
Streptococcus agalactiae H36B
Streptococcus agalactiae NEM316
In the case of Lactobacillus brevis ATCC367 cydC has degenerated to a pseudo gene. Streptococcus agalactiae NEM316 has four open reading frames (gbs1787-1784) with a high similarity to cydABCD of Lactococcus lactis MG1363 and a similar operon structure. Lactobacillus casei ATCC334 possesses, besides a cydABCD- operon, a separate fusion gene of cydA and cydB. The genome of Streptococcus agalactiae H36B contains 3 genes that are annotated as cydA Of these, SAI_1857 lies in an operon together with cydBCD while SAI_1865 and SAI_1866 are next to each other on the chromosome. SAI_1865 and SAI_1866 are truncated versions of cydA and are unlikely to encode a functional subunit I of the bd-type cytochrome.
Although, there is some confusion in the annotation of the open reading frames as either cydC or cydD genes among the lactic acid bacteria, the presence or absence of all four if the cyd-genes could be unambiguously determined for the studied sequenced genomes.
We compared the responses to heme (and menaquinone) (both observed in this work and reported in literature) with the genomic presence of the cydABCD genes and menaquinone biosynthesis. For the sequenced species Lactococcus lactis MG1363, SK11, Lactobacillus plantarum WCFS1, Enterococcus faecalis V583, Streptococcus agalactiae NEM316 there is a match between genotype and phenotype. Heme enhanced aerobic growth (biomass) has also been observed for Oenococcus oeni (A. Gruss presented at the LAB9 congress, Egmond aan Zee, 31 Aug–4 Sep, 2008). These species show respiration behavior (either biomass stimulation or formation of cytochromes) and have cyd-genes present on their genomes. Furthermore, as mentioned, Lactococcus lactis is known to produces menaquinones, whereas both Lactobacillus plantarum WCFS1 and Streptococcus agalactiae NEM316 lack many genes typically involved in menaquinone biosynthesis http://www.kegg.com. This is thus also in line with our observations of the dependency on both heme and menaquinone. Also relevant, in this respect is that we did not observe that heme stimulated biomass formation in Lactobacillus sakei 23K, Lactobacillus delbrueckii B1799 (not sequenced) or in Pediococcus pentosaceus DSM 20333.
There are some discrepancies however, as the sequenced Leuconostoc mesenteroides ATCC 8239 has all four cyd-genes and menaquinone biosynthesis genes, but in our hands, did not show enhanced production of biomass, in the presence of heme (and menaquinone). Heme-induced cytochrome formation has, however, been reported for other strains of Leuconostoc mesenteroides . Furthermore, Enterococcus faecalis B145 required both heme and menaquinone, while the sequenced strain Enterococcus faecalis V538 appears to have a complete menaquinone biosynthesis pathway http://www.kegg.com.
Menaquinone production by Lactococcus lactis MG1363
Menaquinone (K2) production by Lactococcus lactis MG1363.
Menaquinone content (μg/L)
Respiration is species-specific
The presence or absence of the cyd-genes in various species is remarkably consistent, as shown in table 4 and the corresponding text. The cyd-genes were not present in the (completely sequenced) genomes of any of the strains of Streptococcus pyogenes (13), Streptococcus pneumoniae (11), Streptococcus suis (2), Streptococcus thermophilus (3) and Lactobacillus delbrueckii (2), but consistently present in all Streptococcus agalactiae (8), Lactococcus lactis (3), Lactobacillus reuteri (2) and Oenococcus oeni (2) strains. Furthermore, in two separate studies 43 strains of Lactobacillus plantarum were genotyped and their genomic content compared to the genome of Lactobacillus plantarum WCFS1. In all these 43 genomes the cydABCD operon was determined to be present  (and Tseneva, personal communication). To determine if the respiratory-phenotype is as consistent as the genotype, we tested 88 strains of Lactococcus lactis (including SK11, MG1363 and IL1403) and 20 strains of Lactobacillus plantarum (including WCFS1). Heme (and vitamin K2) induced the respiratory response (enhanced biomass formation) in 95% of the Lactococcus lactis strains, and in 80% of the Lactobacillus plantarum strains (data not shown). One of the 4 Lactococcus lactis strains that did not respond to heme was the sequenced strain IL1403. In this particular case, we observed that a transposase is situated directly in front of the cyd-genes on the genome, which could be responsible for this lack of heme-induced response. For the other 3 Lactococcus lactis strains, that did not respond to the presence of heme, no extensive genomic information is available. Both the genotypic data and the growth experiments indicate that respiration is characteristic for a diverse group of lactic acid bacterial species.
High-throughput respiration screening
By using an insertion knock-out bank of Lactococcus lactis B1157, we show that high throughput screening, in 96-well plates, is possible to isolate heme-stimulated lactic acid bacteria . Approximately 8000 insertion mutants were aerobically incubated (with or without heme) and screened on biomass yield.
Disrupted genes in the Lactococcus lactis B1157 respiration negative mutants.
sequence length (bp)
match Length (bp)
Genomic features of disruption location
Geranylgeranyl pyrophosphate synthase
menA, 4-hydroxybenzoate polyprenyltransferase and related prenyltransferases
putative RNA methyltransferase
putative glycosyl hydrolases
noxA, NADH dehydrogenase, FAD-containing subunit
menX, menaquinone biosynthesis related protein
menE, Acyl-CoA synthetases (AMP-forming)/AMP-acid ligases II
menC, o-succinylbenzoate synthase
menC, o-succinylbenzoate synthase
cydD, cytochrome D ABC transporter ATP binding and permease protein
cydD, cytochrome D ABC transporter ATP binding and permease protein
cydB, cytochrome d ubiquinol oxidase, subunit II
aroB, 3-dehydroquinate synthase
aroE, hikimate 5-dehydrogenase
Five of the isolated respiration mutants carried mutations in genes involved in menaquinone biosynthesis. Respiration mutants with disruptions of aroB and aroE are also likely to suffer from an impaired menaquinone biosynthesis, since these genes are involved in synthesis of chorismate, the menaquinone precursor molecule. Three mutants were found that carried disruptions in the cyd-genes that are obviously essential to synthesize the bd-type cytochrome. Furthermore, we have now experimental evidence that a disruption of noxA, annotated as a NADH-dehydrogenase is directly linked to a respiration negative phenotype. 11 out of 13 respiration mutants carry mutations in genes that can be readily explained and thus validate this high throughput method to screen for respiration in lactic acid bacteria.
Lactococcus lactis MG1363 is capable of true respiration, as shown by the formation of a proton motive force by its heme-dependent electron transport chain . We have used the characteristic phenotype of respiring Lactococcus lactis, a higher biomass with less extensive acidification, to screen for other possibly respiring lactic acid bacteria. Besides increased biomass production, respiration includes other traits, such as enhanced robustness. This makes the observation, that certain lactic acid bacteria are respirators, relevant for industrial applications [15, 16]. Induction respiratory behaviour requires supplementation with heme and menaquinone (vitamin K2) in several additional species of lactic acid bacteria.
In the many cases, the heme-stimulated species showed enhanced biomass formation without a higher final pH. In these cases, although heme enhances aerobic growth, possibly as a result of energy conservation and the protection against oxidative stress afforded by the electron transport chain, changes in type of acids produced seems less important.
The addition of heme and menaquinone to the growth medium, to induce respiration in several lactic acid bacteria, may appear contrived. However, plants, the natural source of isolation of many lactic acid bacteria, can provide both heme and menaquinone (A. Gruss presented at the LAB9 congress, Egmond aan Zee, 31 Aug–4 Sep, 2008, and personal communications).
The cyd-genes (cydABCD) are present in many species of lactic acid bacteria. Most sequenced lactic acid bacteria that were screened showed a match between their genotype (cyd-genes, menaquinone biosynthesis genes) and the heme (and menaquinone) induced phenotype. Also the dependence and independence of a menaquinone source, in for example the Lactobacillus species and Lactococcus species, can be explained for some cases, with the presence/absence of menaquinone biosynthesis.
The cyd-genes are not confined to a limited subset of (closely related) species of lactic acid bacteria. In fact, the cyd-genes are present in many species that together span the diversity-range found in lactic acid bacteria . What is remarkable is that the cyd-genes are so consistently present (or absent) in all the (sequenced) strains of a certain species, as can be clearly seen for the members of the genus Streptococcus. This uniformity may be the result of a bias in the isolation of the strains from highly similar niches. We have, however, screened a large number of Lactobacillus plantarum and Lactococcus lactis strains that were isolated from a variety of both industrial and plant-sources (see the materials and methods section). In both cases the induction of respiration by addition of heme and menaquinone was highly uniform with only a few exceptions. We can conclude that respiration is characteristic trait for, at least, Lactococcus lactis and Lactobacillus plantarum.
The high throughput screening of 8000 insertion mutants of Lactococcus lactis revealed that a high proportion of the respiration-impaired mutants contained insertions in menaquinone-biosynthesis genes. This implies that such methods can be used to screen for menaquinone producers among lactic acid bacteria. Those lactic acid bacteria that are stimulated by heme alone are potential producers of menaquinones.
Roughly half of the sequenced lactic acid bacteria contain the cydABCD genes. We investigated whether such a distribution could best be explained by horizontal gene transfer or, alternatively, by gene loss. The phylogenetic tree, constructed with the cyd genes sequences (Fig 2) is highly similar to the canonical (16S rRNA) evolutionary tree. Thus all lactic acid bacteria group together in one separate branch, which indicates ancient origins of the bd-type cytochrome. The results presented here not only support the idea that the cyd genes were present in the common ancestor of lactic acid bacteria, but in fact of all Firmicutes. Thus gene loss events best explains the observed cyd-gene distribution amongst lactic acid bacteria, which is in line with their highly auxotrophic nature. Lactic acid bacteria as a group have a history of adaptation to nutrient rich food-environments and progressive gene-loss that was nicely visualised by Makarova et.al. . A typical example of this process is the extensive gene decay (high abundance of pseudo-genes) in the yoghurt-bacterium Streptococcus thermophilus .
(Mena)quinones are best known as cofactors of bacterial respiratory chains, shuttling electrons from dehydrogenases to the terminal oxidase. Menaquinone production in anaerobic, non-heme supplemented conditions have been reported in literature before for other Lactococcus lactis strains and Leuconostoc sp. . Several groups have proposed an additional role of menaquinones in offering protection against oxidative stress [37, 38]. Recently it has been shown that quinones of Lactococcus lactis can reduce metal-ions such as Fe3+ and Cu2+, which may facilitate their assimilation . Still, contrary to expectations when Lactococcus lactis was grown aerobically (both with and without heme), the total amount of menaquinones produced was almost two-fold lower compared with anaerobic conditions. Furthermore we observed that aerobic cultivation induces an altered composition of the menaquinone pool, with a shift towards menaquinones with more 9–10 isoprenoid residues in their side-chain. This study reports that respiration in several lactic acid bacteria can be induced by a combination of heme and vitamin K2(4) (with four isoprenoid residues). It is thus not known what function the observed shift, in the composition of the menaquinone-pool to menaquinones with a longer side-chain length, serves in these bacteria. In humans, however, menaquinones with longer side-chain remain detectable for longer times in the blood stream and may form a more available source of vitamin K2 . Therefore, induction of the production of menaquinone with longer side-chains by lactic acid bacteria may better fulfil human vitamin K2 requirements. The function of menaquinones, in the (anaerobic) metabolism of Lactococcus lactis, is unclear. For example, the various menaquinone mutants of Lactococcus lactis grew well anaerobically and aerobically (data not shown). In fact many species of lactic acid bacteria grow well both anaerobically as aerobically, although not all of these produce menaquinones. Since, lactic acid bacteria do not depend on menaquinone for growth they make ideal organisms to study the impact of the menaquinones, with various side-chain lengths, on (respiratory) metabolism.
This work has revealed that a number of known lactic acid bacteria are potential respirators which, as in the case of Lactococcus lactis, could be targeted for future industrial exploitation.
We wish to acknowledge Jan Hoolwerf for the 16S rRNA verification of many of the lactic acid bacterial species used in this work. The Kluyver Centre is financially supported by the Netherlands Genomics Initiative (NGI).
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