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lactb

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Official Full Name
lactamase, beta
Background
This gene encodes a protein from the large 39S subunit of the mitochondrial ribosome (mitoribosome). The encoded protein has some sequence similarity to prokaryotic beta-lactamases but most of the residues that are responsible for the beta-lactamase activity are not conserved between the two proteins. Two alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.
Synonyms
LACTB; lactamase, beta; mitochondrial ribosomal protein L56 , MRPL56; serine beta-lactamase-like protein LACTB, mitochondrial; FLJ14902; mitochondrial ribosomal protein L56; mitochondrial 39S ribosomal protein L56; serine beta lactamase-like protein LACTB; AmpA; AmpC; Cephalosporinase; beta-lactamas; cefinase; b-Lactamase, Bacillus cereus 569/H9; Lactamase, beta-; B-LACTAMASE; Recombinant Beta Lactamase; Carbapenem hydrolase; Carbapenemase; Cefotaximase; Ceftazidimase; Ceftazimidase; Cefuroximase; Cephamyci; Beta-lactamases; beta-lactamase domain; Type IV beta-lactamase; Enterobacter cloacae; EC 3.5.2.6; Bacteria; Proteobacteria; Gamma Proteobacteria; Enterobacteriales; Enterobacteriaceae; Enterobacter; E. c. subsp. cloacae; E. c. subsp. dissolvens; Bacillus cloacae; Bacterium cloacae; Cloaca cloacae; Aerobacter cloacae; Erwinia dissolvens; Pseudomonas dissolvens; Bacterium dissolvens; Phytomonas dissolvens; Aplanobacter dissolvens; Aerobacter dissolvens; Enterobacter dissolvens; zgc:110419

Recent Progress

LACTB gene encodes the 54 kDa protein LACTB, which shares significant sequence similarity to serine proteases of the penicillin binding protein and beta-lactamase superfamily existing in bacteria. LACTB is associated with the regulation of the metabolic circuitry. This protein is widely studies due to its relationship with diseases. Researchers have already discovered a causal association between LACTB and obesity. LACTB also play a role in tumor suppressing by modulating lipid metabolism in breast cancer. This role of LACTB also believed to be functioning through its effect on mitochondrial phospholipid metabolism and modulation of cell differentiation state. It has been suggested LACTB could promote intra-mitochondrial membrane organization, regulate electron transport chain complex I, and control cellular metabolism(Fig. 1).

Fig. 1. Three-dimensional model of LACTB shows the position of the predicted coiled-coil segment (yellow arrows), and the side chains of the catalytic site residues (yellow). (Z Polianskyte et al, 2009)

Through gene expression profiles, researchers revealed that, compared with muscle progenitor cells, LACTB was overexpressed in differentiated, post-mitotic muscle cells. After the study of 18 breast cancer cell lines, researchers proposed that LACTB overexpression decreased proliferation in breast cancer cell lines and LACTB induction invoked tumor regression in vivo. More specifically, LACTB expression promoted epithelial differentiation of breast cancer cells and reduced expression of the mitochondrial phospholipids lysophosphatidylethanolamines (LPE) and phosphatidylethanolamines (PE). Further findings also suggested that LACTB controls proliferation and differentiation, through regulation of mitochondrial phospholipids.

Another group of researchers was able to propose that the LACTB potently inhibits the proliferation of breast cancer cells, with in vitro and in vivo studies in mice and humans. The specific mechanism involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. Researchers believed that this mechanism is achieved, to some extent, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase.

In order to identify the upregulated genes in differentiated post-mitotic human and murine muscle cells as compared to their actively cycling progenitors, researchers conducted a microarray analysis. LACTB overexpression had the biggest influence on decreasing the rate of proliferation of breast cancer cell lines, but only had only minimal effect on the proliferation of non-tumorigenic cell lines. Moreover, LACTB were downregulated in over a third of breast cancer tissues out of 714 clinical samples. There has been complete disappearance of the tumour mass, suggesting that exogenous expression of LACTB in already-formed tumors caused tumor regression. These findings taken together further confirmed that the protease LACTB is a novel tumour suppressor, functioning through the control of mitochondrial lipid metabolism.

Moreover, through the mouse studies in vitro, researchers were able to suggest that a fluorescent substrate of the Mycobacterium tuberculosis enzyme LACTB could be a useful TB(tuberculosis) diagnostic marker. In the macrophages of cultured M. tuberculosis–infected mouse, the fluorescent substrate produced a signal that could be associated with bacterial number, compared with uninfected cells. Still in the cultured M. tuberculosis–infected mouse, compared with no treatment, a TB therapeutic resulted in a decreased fluorescence signal. Based on the findings above, further steps including further development of in vitro assays using the fluorescent substrate may be carried out. It has been reported that at least eight companies have LACTB inhibitors in development stages, ranging from preclinical to marketed for a variety of bacterial infections.

References:

  1. "LACTB May Be a Tumor Suppressor Gene in Breast Cancer." Cancer Discovery 7.6(2017):OF23.
  2. Keckesova Z, et al. "LACTB is a tumour suppressor that modulates lipid metabolism and cell state." Nature 543.7647(2017):681.
  3. Cucchi, Danilo, and C. Mauro. "LACTB-mediated tumour suppression by increased mitochondrial lipid metabolism." Cell Death & Differentiation 24.7(2017).
  4. Eriksson, Ove, M. Lalowski, and D. Lindholm. "Commentary: LACTB is a tumour suppressor that modulates lipid metabolism and cell state:." Frontiers in Physiology 8(2017).
  5. "β-Lactamase (LACTB) reporter enzyme fluorescence (REF) to detect tuberculosis (TB) infection." Nature 26(2013).