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Gene Review

LACTB  -  lactamase, beta

Homo sapiens

Synonyms: FLJ14902, G24, MRPL56, Serine beta-lactamase-like protein LACTB, mitochondrial, UNQ843/PRO1781
 
 

Overview

Horizontal gene transfer from endosymbionts to eukaryotes seems a likely evolutionary trajectory by which this erstwhile bacterial peptidase has been adapted to non-catalytic roles in plants and metazoans. At what point it became a constitutive component of the mitochondrial molecular architecture, possibly via filament assembly, is less clear. Nevertheless, connections with biochemical functions could provide a unifying mechanistic explanations to underpin what appear to be robust disease and metabolic profile associations.

 

Disease relevance

  • The first indication is from the abstract of "Variations in DNA elucidate molecular networks that cause disease" (2008) "Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits" [1]
  • The RefSeq entry   includes cross references to a number of association studies but some of the results are entombed in supplementary data rather than collated into database entries. Three of these that could be related, mechanistically (even via proxy SNPS) are listed below
  • "Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks" (2009) [2]
  • "Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids" (2010) [3]
  • "Human metabolic individuality in biomedical and pharmaceutical research" (2011) [4]
 

Characterisation data

  • The initial sequencing and characterization for the 551 residue mouse LACTB (2001) recorded the following; a predicted amino-terminal transmembrane domain (subsequently indicated as mitochondrial-targeting) , absence of predicted signal peptide and clear homology to beta-lactamases but not an exact, match to the PROSITE class-C β-lactamase motif. Homologues were detected in rat, cow, rabbit, pig, toad, zebrafish, and Caenorhabditis elegans, but not Saccharomyces cerevisiae or Drosophila melanogaster. The protein mapped to human chromosome 15q22.1 and mouse chromosome 9, with human and mouse transcripts detected ~ 2.3 Kb by Northern blot. [5].
  • Expression of mouse LACTB as a GST fusion protein in E. coli (2006) with evidence of proper folding. [6]
  • Bioinformatic identification of a single serine beta-lactamase-like gene product in the Arabidopsis and rice proteomes (2006), both of which are also predicted to localise to mitochondria. [7]
  • Phylogenetic analysis indicated the LACTB family (2008) may derive from four separate bacterial LPBP-B subclass genes most likely acquired simultaneously from α-proteobacteria by endosymbiont gene transfer. The evolutionary history seems dominated by gene losses resulting in an uneven distribution of LACTB family proteins in metazoan taxa.
  • Inclusion in a (2008) mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues, together with evidence that LACTB was associated with complex I of the electron transport chain (fig. 6). [8]
  • Localisation of LACTB to the mitochondrial intermembrane space (2009) where it is polymerized into stable 100 nM filaments and may thus promote intramitochondrial membrane organization and micro-compartmentalization. [9]
  • PhD Thesis (2009) "Characterization of the mitochondrial active-site serine protein LACTB: filaments in the mitochondrial intermembrane space" Polianskyte, Z. ( 
  • The UniProt annotation includes experimental evidence for phospho serine site occupancy and Lysine acetylation

Erroneous or equivocal information

  • Despite the global persistence of MRPL56 as a synonym in database records since the initial single report, there has been no corroborative evidence that LACTB is a constitutive component of the mitochondrial large ribosomal subunit. This is reflected in the interim HGNC symbol revisions (i.e. LACTB > MRPL56 > LACTB). It is simply too large and the transitive annotation from a single bovine tryptic peptide was likely to have been a co-purification artifact [10]. While the UniProt HNGC/Ensembl axis is concordant with the revision the misleading listing of MRPL56 as a primary function is widespread on the NCBI side, including Entrez Gene and RefSeq.
  • The original inexact match to the extended active site motive derived from enzymatically characterised prokaryotic homologoues indicates that vertebrate LACTB is probably devoid of peptidase activity. While no experimental data has contradicted this conclusion the use of automated homology-based annotation transfer has resulted in the this protein being assigned this unverified proteolytic function effectively across all databases (e.g. in the UniProt GO and MEROPS cross-references).
  • As a search of PubMed will show the bacterial beta-lactamases have been the subject of many papers characterising their enzymology and inhibitor development. However, curatorial oversight, related to name similarity, has resulted in some chemogenomic and research drug target compilations containing database linkages between human LACTB, chemical structures and inhibition data from publications specifying bacterial enzymes. At the time of editing (August 2012) these incorrect mappings have spread widely between databases.
  • An analogous curatorial error is included in the the RefSeq cross-references in the form of a spurious GeneRIF for PMID:17517902.

Related blog post. I have outlined some of my personal learning points from doing these edits at  .

References

  1. Variations in DNA elucidate molecular networks that cause disease. Chen, Y., Zhu, J., Lum, P.Y., Yang, X., Pinto, S., MacNeil, D.J., Zhang, C., Lamb, J., Edwards, S., Sieberts, S.K., Leonardson, A., Castellini, L.W., Wang, S., Champy, M.F., Zhang, B., Emilsson, V., Doss, S., Ghazalpour, A., Horvath, S., Drake, T.A., Lusis, A.J., Schadt, E.E. Nature. (2008) [Pubmed]
  2. Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Yang, X., Deignan, J.L., Qi, H., Zhu, J., Qian, S., Zhong, J., Torosyan, G., Majid, S., Falkard, B., Kleinhanz, R.R., Karlsson, J., Castellani, L.W., Mumick, S., Wang, K., Xie, T., Coon, M., Zhang, C., Estrada-Smith, D., Farber, C.R., Wang, S.S., van Nas, A., Ghazalpour, A., Zhang, B., Macneil, D.J., Lamb, J.R., Dipple, K.M., Reitman, M.L., Mehrabian, M., Lum, P.Y., Schadt, E.E., Lusis, A.J., Drake, T.A. Nat. Genet. (2009) [Pubmed]
  3. Biological, clinical and population relevance of 95 loci for blood lipids. Teslovich, T.M., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Ripatti, S., Chasman, D.I., Willer, C.J., Johansen, C.T., Fouchier, S.W., Isaacs, A., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Aulchenko, Y.S., Thorleifsson, G., Feitosa, M.F., Chambers, J., Orho-Melander, M., Melander, O., Johnson, T., Li, X., Guo, X., Li, M., Shin Cho, Y., Jin Go, M., Jin Kim, Y., Lee, J.Y., Park, T., Kim, K., Sim, X., Twee-Hee Ong, R., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Song, K., Hua Zhao, J., Yuan, X., Luan, J., Lamina, C., Ziegler, A., Zhang, W., Zee, R.Y., Wright, A.F., Witteman, J.C., Wilson, J.F., Willemsen, G., Wichmann, H.E., Whitfield, J.B., Waterworth, D.M., Wareham, N.J., Waeber, G., Vollenweider, P., Voight, B.F., Vitart, V., Uitterlinden, A.G., Uda, M., Tuomilehto, J., Thompson, J.R., Tanaka, T., Surakka, I., Stringham, H.M., Spector, T.D., Soranzo, N., Smit, J.H., Sinisalo, J., Silander, K., Sijbrands, E.J., Scuteri, A., Scott, J., Schlessinger, D., Sanna, S., Salomaa, V., Saharinen, J., Sabatti, C., Ruokonen, A., Rudan, I., Rose, L.M., Roberts, R., Rieder, M., Psaty, B.M., Pramstaller, P.P., Pichler, I., Perola, M., Penninx, B.W., Pedersen, N.L., Pattaro, C., Parker, A.N., Pare, G., Oostra, B.A., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., Meitinger, T., McPherson, R., McCarthy, M.I., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Mangino, M., Magnusson, P.K., Lucas, G., Luben, R., Loos, R.J., Lokki, M.L., Lettre, G., Langenberg, C., Launer, L.J., Lakatta, E.G., Laaksonen, R., Kyvik, K.O., Kronenberg, F., König, I.R., Khaw, K.T., Kaprio, J., Kaplan, L.M., Johansson, A., Jarvelin, M.R., Janssens, A.C., Ingelsson, E., Igl, W., Kees Hovingh, G., Hottenga, J.J., Hofman, A., Hicks, A.A., Hengstenberg, C., Heid, I.M., Hayward, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Gyllensten, U., Guiducci, C., Groop, L.C., Gonzalez, E., Gieger, C., Freimer, N.B., Ferrucci, L., Erdmann, J., Elliott, P., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., Deloukas, P., de Geus, E.J., de Faire, U., Crawford, G., Collins, F.S., Chen, Y.D., Caulfield, M.J., Campbell, H., Burtt, N.P., Bonnycastle, L.L., Boomsma, D.I., Boekholdt, S.M., Bergman, R.N., Barroso, I., Bandinelli, S., Ballantyne, C.M., Assimes, T.L., Quertermous, T., Altshuler, D., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Adair, L.S., Taylor HA, J.r., Borecki, I.B., Gabriel, S.B., Wilson, J.G., Holm, H., Thorsteinsdottir, U., Gudnason, V., Krauss, R.M., Mohlke, K.L., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Rotter, J.I., Boerwinkle, E., Strachan, D.P., Mooser, V., Stefansson, K., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., van Duijn, C.M., Peltonen, L., Abecasis, G.R., Boehnke, M., Kathiresan, S. Nature. (2010) [Pubmed]
  4. Human metabolic individuality in biomedical and pharmaceutical research. Suhre, K., Shin, S.Y., Petersen, A.K., Mohney, R.P., Meredith, D., Wägele, B., Altmaier, E., Deloukas, P., Erdmann, J., Grundberg, E., Hammond, C.J., de Angelis, M.H., Kastenmüller, G., Köttgen, A., Kronenberg, F., Mangino, M., Meisinger, C., Meitinger, T., Mewes, H.W., Milburn, M.V., Prehn, C., Raffler, J., Ried, J.S., Römisch-Margl, W., Samani, N.J., Small, K.S., Wichmann, H.E., Zhai, G., Illig, T., Spector, T.D., Adamski, J., Soranzo, N., Gieger, C. Nature. (2011) [Pubmed]
  5. Identification, genomic organization, and mRNA expression of LACTB, encoding a serine beta-lactamase-like protein with an amino-terminal transmembrane domain. Smith, T.S., Southan, C., Ellington, K., Campbell, D., Tew, D.G., Debouck, C. Genomics. (2001) [Pubmed]
  6. Expression and purification of the mitochondrial serine protease LACTB as an N-terminal GST fusion protein in Escherichia coli. Liobikas, J., Polianskyte, Z., Speer, O., Thompson, J., Alakoskela, J.M., Peitsaro, N., Franck, M., Whitehead, M.A., Kinnunen, P.J., Eriksson, O. Protein. Expr. Purif. (2006) [Pubmed]
  7. Cross genome comparisons of serine proteases in Arabidopsis and rice. Tripathi, L.P., Sowdhamini, R. BMC. Genomics. (2006) [Pubmed]
  8. A mitochondrial protein compendium elucidates complex I disease biology. Pagliarini, D.J., Calvo, S.E., Chang, B., Sheth, S.A., Vafai, S.B., Ong, S.E., Walford, G.A., Sugiana, C., Boneh, A., Chen, W.K., Hill, D.E., Vidal, M., Evans, J.G., Thorburn, D.R., Carr, S.A., Mootha, V.K. Cell. (2008) [Pubmed]
  9. LACTB is a filament-forming protein localized in mitochondria. Polianskyte, Z., Peitsaro, N., Dapkunas, A., Liobikas, J., Soliymani, R., Lalowski, M., Speer, O., Seitsonen, J., Butcher, S., Cereghetti, G.M., Linder, M.D., Merckel, M., Thompson, J., Eriksson, O. Proc. Natl. Acad. Sci. U. S. A. (2009) [Pubmed]
  10. The large subunit of the mammalian mitochondrial ribosome. Analysis of the complement of ribosomal proteins present. Koc, E.C., Burkhart, W., Blackburn, K., Moyer, M.B., Schlatzer, D.M., Moseley, A., Spremulli, L.L. J. Biol. Chem. (2001) [Pubmed]
 
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