Skip to main content
SpringerLink
Log in

Evolutionary History of d-Lactate Dehydrogenases: A Phylogenomic Perspective on Functional Diversity in the FAD Binding Oxidoreductase/Transferase Type 4 Family

  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

Lactate dehydrogenases which convert lactate to pyruvate are found in almost every organism and comprise a group of highly divergent proteins in amino acid sequence, catalytic properties, and substrate specificity. While the l-lactate dehydrogenases are among the most studied enzymes, very little is known about the structure and function of d-lactate dehydrogenases (d-LDHs) which include two discrete classes of enzymes that are classified based on their ability to transfer electrons and/or protons to NAD in NAD-dependent lactate dehydrogenases (nLDHs), and FAD in NAD-independent lactate dehydrogenases (iLDHs). In this study, we used a combination of structural and phylogenomic approaches to reveal the likely evolutionary events in the history of the recently described FAD binding oxidoreductase/transferase type 4 family that led to the evolution of d-iLDHs (commonly referred as DLD). Our phylogenetic reconstructions reveal that DLD genes from eukaryotes form a paraphyletic group with respect to d-2-hydroxyglutarate dehydrogenase (D2HGDH). All phylogenetic reconstructions recovered two divergent yeast DLD phylogroups. While the first group (DLD1) showed close phylogenetic relationships with the animal and plant DLDs, the second yeast group (DLD2) revealed strong phylogenetic and structural similarities to the plant and animal D2HGDH group. Our data strongly suggest that the functional assignment of the yeast DLD2 group should be carefully revisited. The present study demonstrates that structural phylogenomic approach can be used to resolve important evolutionary events in functionally diverse superfamilies and to provide reliable functional predictions to poorly characterized genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ADAS:

Alkyldihydroxyacetone phosphate synthase

ALO:

d-Arabinono-1,4-lactone oxidase

CKX:

Cytokinin dehydrogenase

DIM:

Diminuto like protein

d-LDH:

d-Lactate dehydrogenase

DLD:

d-Lactate dehydrogenase [cytochrome] 1

D2HGDH:

d-2-Hydroxyglutarate dehydrogenase

DHC24:

24-Dehydrocholesterol reductase

FAD:

Flavin adenine dinucleotide

GGLO:

l-Gulanolactone oxidase

PCMH:

p-Cresol methylhydroxylase

RETO:

Reticuline oxidase

MurB:

UDP-N-acetylenolpyruvylglucosamine reductase

VAOX:

Vanillyl-alcohol oxidase

References

  • Achouri Y, Noël G, Vertommen D, Rider MH, Veiga-Da-Cunha M, Van Schaftingen E (2004) Identification of a dehydrogenase acting on d-2 hydroxyglutarate. Biochem J 381:35–42

    Article  PubMed  CAS  Google Scholar 

  • Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402

    Article  PubMed  CAS  Google Scholar 

  • Baker PJ, Sawa Y, Shibata H, Sedelnikova SE, Rice DW (1998) Analysis of the structure and substrate binding of Phormidium lapideum alanine dehydrogenase. Nat Struct Mol Biol 5:561–567

    Article  CAS  Google Scholar 

  • Blank LM, Kuepfer L, Sauer U (2005) Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast. Genome Biol 6:R49

    Article  PubMed  Google Scholar 

  • Bongaerts G, Bakkeren J, Severijnen R, Sperl W, Willems H, Naber T, Wevers R, van Meurs A, Tolboom J (2000) Lactobacilli and acidosis in children with short small bowel. J Pediatr Gastroenterol Nutr 30:288–293

    Article  PubMed  CAS  Google Scholar 

  • Chelstowska A, Liu Z, Jia Y, Amberg D, Butow RA (1999) Signaling between mitochondria and the nucleus regulates the expression of a new d-lactate dehydrogenase activity in yeast. Yeast 15:1377–1391

    Article  PubMed  CAS  Google Scholar 

  • Chothia C (1992) Proteins. One thousand families for the molecular biologists. Nature 420:218–223

    Google Scholar 

  • Cox B, Kislinger T, Emili A (2005) Integrating gene and protein expression data: pattern analysis and profile mining. Methods 35:303–314

    Article  PubMed  CAS  Google Scholar 

  • Cristescu ME, Innes DJ, Stillman JH, Crease TJ (2008) d- and l-lactate dehydrogenases during invertebrate evolution. BMC Evol Biol 8:268

    Article  PubMed  Google Scholar 

  • Cunane LM, Chen ZW, Shamala N, Mathews FS, Cronin CN, McIntire WS (2000) Structures of the flavocytochrome p-cresol methylhydroxylase and its enzyme-substrate complex: gated substrate entry and proton relays support the proposed catalytic mechanism. J Mol Biol 295:357–374

    Article  PubMed  CAS  Google Scholar 

  • Dengler U, Niefind K, Kiess M, Schomburg D (1997) Crystal structure of a ternary complex of d-2-hydroxyisocaproate dehydrogenase from Lactobacillus casei, NAD+ and 2-oxoisocaproate at 1.9 A resolution. J Mol Biol 267:640–660

    Article  PubMed  CAS  Google Scholar 

  • Dym O, Eisenberg D (2001) Sequence-structure analysis of FAD-containing proteins. Protein Sci 10:1712–1728

    Article  PubMed  CAS  Google Scholar 

  • Dym O, Pratt EA, Ho C, Eisenbert D (2000) The crystal structure of d-lactate dehydrogenase, a peripherals membrane respiratory enzyme. Proc Natl Acad Sci USA 97:9413–9418

    Article  PubMed  CAS  Google Scholar 

  • Eisen JA (1998) Phylogenomics: improving functional predictions for uncharacterized genes by evolutionary analysis. Genome Res 8:163–167

    PubMed  CAS  Google Scholar 

  • Ewaschuk JB, Naylor JM, Zello GA (2005) d-lactate in human and ruminant metabolism. J Nutr 135:1619–1625

    PubMed  CAS  Google Scholar 

  • Fraaije MW, van Berkel WJH, Benen JAE, Visser J, Mattevi A (1998) A novel oxidoreductase family sharing a conserved FAD-binding domain. Trends Biochem Sci 23:206–207

    Article  PubMed  CAS  Google Scholar 

  • Glasner ME, Gerlt JA, Babbitt PC (2006) Evolution of enzyme superfamilies. Curr Opin Chem Biol 10:492–497

    Article  PubMed  CAS  Google Scholar 

  • Goffin P, Lorquet F, Kleerebezem M, Hols P (2004) Major role of NAD-dependent lactate dehydrogenases in aerobic lactate utilization in Lactobacillus plantarum during early stationary phase. J Bacteriol 186:6661–6666

    Article  PubMed  CAS  Google Scholar 

  • Goldberg JD, Yoshida T, Brick P (1994) Crystal structure of a NAD-dependent d-glycerate dehydrogenase at 2.4 Å resolution. J Mol Biol 236:1123–1140

    Article  PubMed  CAS  Google Scholar 

  • Gu Z, Steinmetz LM, Gu X, Scharfe C, Davis RW, Li WH (2003) Role of duplicate genes in genetic robustness against null mutations. Nature 421:63–66

    Article  PubMed  CAS  Google Scholar 

  • Hove H (1998) Lactate and short chain fatty acid production in the human colon: implications for d-lactic acidosis, short-bowel syndrome, antibiotic associated diarrhoea, colonic cancer, and inflammatory bowel disease. Dan Med Bull 45:15–33

    PubMed  CAS  Google Scholar 

  • Kuehnle K, Crameri A, Kälin RE, Luciani P, Benvenuti S, Peri A, Ratti F, Rodolfo M, Kulic L, Heppner FL, Nitsch RM, Mohajeri MH (2008) Prosurvival effect of DHCR24/Seladin-1 in acute and chronic responses to oxidative stress. Mol Cell Biol 28:539–550

    Article  PubMed  CAS  Google Scholar 

  • Kumar V, Carlson JE, Ohgi KA, Edwards TA, Rose DW, Escalante CR et al (2002) Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase. Mol Cell 10:857–869

    Article  PubMed  CAS  Google Scholar 

  • Lamzin VS, Dauter Z, Popov VO, Harutyunyan EH, Wilson KS (1994) High resolution structures of holo and apo formate dehydrogenase. J Mol Biol 236:759–785

    Article  PubMed  CAS  Google Scholar 

  • Lamzin VS, Dauter Z, Wilson KS (1995) How Nature deals with stereoisomers. Curr Opin Struct Biol 5:830–836

    Article  PubMed  CAS  Google Scholar 

  • Leferink NG, Heuts DP, Fraaije MW, van Berkel WJ (2008) The growing VAO flavoprotein family. Arch Biochem Biophys 474:292–301

    Article  PubMed  CAS  Google Scholar 

  • Markert CL, Shaklee JB, Whitt GS (1975) Evolution of a gene. Science 189:102–114

    Article  PubMed  CAS  Google Scholar 

  • Möller W, Amons R (1985) Phosphate-binding sequences in nucleotide-binding proteins. FEBS Lett 186:1–7

    Article  PubMed  Google Scholar 

  • Ogata M, Arihara K, Yagi T (1981) d-Lactate dehydrogenase of Desulfovibrio vulgaris. J Biochem 89:1423–1431

    PubMed  CAS  Google Scholar 

  • Presgraves DC (2005) Evolutionary genomics: new genes for new jobs. Curr Biol 15:R52–R53

    Article  PubMed  CAS  Google Scholar 

  • Reed DW, Hartzell PL (1999) The Archaeoglobus fulgidus d-lactate dehydrogenase is a Zn2+ flavoprotein. J Bacteriol 181:7580–7587

    PubMed  CAS  Google Scholar 

  • Ronquist F, Huelsenbeck JP (2003) MRBAYES 3: Bayesian phylogenetic inference under mixed models. Bioinformatics 19:1572–1574

    Article  PubMed  CAS  Google Scholar 

  • Rozen S, Skaletsky HJ (1998) Primer3. Code available at http://www-genome.wi.mit.edu/genome_software/other/primer3.html

  • Rutledge RG (2004) Sigmoidal curve-fitting redefines quantitative real-time PCR with the prospective of developing automated high-throughput applications. Nucleic Acids Res 32:e178

    Article  PubMed  CAS  Google Scholar 

  • Rutledge RG, Stewart D (2008) A kinetic-based sigmoidal model for the polymerase chain reaction and its application to high-capacity absolute quantitative real-time PCR. BMC Biotechnol 8:47

    Article  PubMed  Google Scholar 

  • Stein L (2001) Genome annotation: from sequence to biology. Nature Rev 2:493

    CAS  Google Scholar 

  • Struys EA, Korman SH, Salomons GS, Darmin PS, Achouri Y, van Schaftingen E, Verhoeven NM, Jakobs C (2005) Mutations in phenotypically mild d-2-hydroxyglutaric aciduria. Ann Neurol 58:626–630

    Article  PubMed  CAS  Google Scholar 

  • Swofford DL (2003) PAUP* Phylogenetic analysis using parsimony and other methods, version 4.0 Sinauer, Sunderland

  • Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680

    Article  PubMed  CAS  Google Scholar 

  • Thornton JW, DeSalle R (2000) Gene family evolution and homology: genomics meets phylogenetics. Annu Rev Genomics Hum Genet 1:41–73

    Article  PubMed  CAS  Google Scholar 

  • Tian Q, Stepaniants SB, Mao M, Weng L, Feetham MC et al (2004) Integrated genomic and proteomic analyses of gene expression in Mammalian cells. Mol Cell Proteomics 3:960–969

    Article  PubMed  CAS  Google Scholar 

  • Tobey KL, Grant GA (1986) The nucleotide sequence of the serA gene of Escherichia coli and the amino acid sequence of the encoded protein d-3-phosphoglycerate dehydrogenase. J Biol Chem 261:12179–12183

    PubMed  CAS  Google Scholar 

  • Whelan S, Goldman N (2001) A general empirical model of protein evolution derived from multiple protein families using a maximum-likelihood approach. Mol Biol Evol 18:691–699

    PubMed  CAS  Google Scholar 

  • Wierenga RK, Drenth J, Schulz GE (1983) Comparison of the threedimensional protein and nucleotide structure of the FAD-binding domain of p-hydroxybenzoate hydroxylase with the FAD- as well as NADPH-binding domains of glutathione reductase. J Mol Biol 167:725–739

    Article  PubMed  CAS  Google Scholar 

  • Zdobnov EM, Apweiler R (2001) InterProScan—an integration platform for the signature-recognition methods in InterPro. Bioinformatics 17:847–848

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank A. Constantin and B. Komnenov for helping with the manual annotation of the D. pulex genes. We also thank A. Warner and three anonymous reviewers for providing constructive comments. The sequencing and annotation of the D. pulex sequences were performed at the DOE Joint Genome Institute in collaboration with the Daphnia Genomics Consortium. This work was supported by the Great Lakes Institute for Environmental Research postdoctoral fellowship to EEE and by the Natural Sciences and Engineering Research Council of Canada (NSERC) grants to MEC.

Author information

Authors and Affiliations

  1. University of Windsor, Great Lakes Institute for Environmental Research, 401 Sunset Ave., Windsor, Ontario, N9B 3P4, Canada

    Melania E. Cristescu & Emmanuel E. Egbosimba

Authors
  1. Melania E. Cristescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emmanuel E. Egbosimba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melania E. Cristescu.

Additional information

All sequences produced in this work have been deposited to GenBank (GQ199601; GQ199602; GQ199603; GQ199604).

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 58 kb)

(DOC 40 kb)

(DOC 149 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cristescu, M.E., Egbosimba, E.E. Evolutionary History of d-Lactate Dehydrogenases: A Phylogenomic Perspective on Functional Diversity in the FAD Binding Oxidoreductase/Transferase Type 4 Family. J Mol Evol 69, 276–287 (2009). https://doi.org/10.1007/s00239-009-9274-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-009-9274-x

Keywords

Search

Navigation