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Bacterial Hormone-Sensitive Lipases (Bhsls): Emerging Enzymes for Biotechnological Applications T

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Bacterial Hormone-Sensitive Lipases (Bhsls): Emerging Enzymes for Biotechnological Applications T J. Microbiol. Biotechnol. (2017), 27(11), 1907–1915 https://doi.org/10.4014/jmb.1708.08004 Research Article Review jmb Bacterial Hormone-Sensitive Lipases (bHSLs): Emerging Enzymes for Biotechnological Applications T. Doohun Kim* Department of Chemistry, College of Natural Science, Sookmyung Women’s University, Seoul 04310, Republic of Korea Received: August 3, 2017 Revised: September 11, 2017 Lipases are important enzymes with biotechnological applications in dairy, detergent, food, Accepted: September 16, 2017 fine chemicals, and pharmaceutical industries. Specifically, hormone-sensitive lipase (HSL) is First published online an intracellular lipase that can be stimulated by several hormones, such as catecholamine, October 14, 2017 glucagon, and adrenocorticotropic hormone. Bacterial hormone-sensitive lipases (bHSLs), *Corresponding author which are homologous to the C-terminal domain of HSL, have α/β-hydrolase fold with a Phone: +82-2-2077-7806; catalytic triad composed of His, Asp, and Ser. These bHSLs could be used for a wide variety of Fax: +82-2-2077-7321; E-mail: doohunkim@sookmyung. industrial applications because of their high activity, broad substrate specificity, and ac.kr remarkable stability. In this review, the relationships among HSLs, the microbiological origins, the crystal structures, and the biotechnological properties of bHSLs are summarized. pISSN 1017-7825, eISSN 1738-8872 Keywords: Hormone-sensitive lipase, cap domain, promiscuity, substrate specificities, Copyright© 2017 by The Korean Society for Microbiology industrial applications and Biotechnology Introduction hormone (ACTH), and glucagon [10, 11]. The activity of HSL is regulated by reversible cAMP-dependent phosphorylation Lipases (triacylglycerol hydrolases, E.C. 3.1.1.3) catalyze [12]. In adipose tissue, HSL catalyzes the breakdown steps the hydrolysis of lipids or lipid-related compounds, which of triacylglycerol and diacylglycerol, which promotes the could release free fatty acids (FFAs), diacylglycerols, release of FFAs for transport to other organs as a major monoacylglycerols, and glycerols in the mobilization source of energy. In addition, HSL has been shown to process of fats or oils [1, 2]. In addition, these enzymes, hydrolyze or synthesize a broad range of substrates which are widespread in all three domains of life, are also containing ester linkages, which include cholesteryl esters, involved in synthetic reactions such as esterification, esters of steroid hormones, retinyl esters, and other lipid- transesterification, alcoholysis, or acidolysis [3, 4]. Most related substrates [13, 14]. This broad substrate specificity lipases belong to the α/β-hydrolase superfamily, which is makes them highly attractive for industrial applications. supposed to have a reaction mechanism similar to that of HSL has been comprehensively studied in mammalian serine proteases [5, 6]. In addition to their physiological species, and three isoforms are known, ranging in size from roles, lipases are highly useful for industrial applications in 84 to 130 kDa [15]. The human HSL enzyme is composed of a dairy, food, pharmaceutical, cosmetic, biofuel, and fine 786-amino-acid polypeptide without any membrane-spanning chemical industries owing to their high stability, broad region. This enzyme could form functional aggregates at substrate specificity, high regio-/stereo-selectivity, and high concentrations as well as bind to phospholipid vesicles remarkable stability [7-9]. Moreover, there are still great for its function [11, 13]. Using biochemical and biophysical demands for new lipases with great stability, high methods, including sedimentation analyses, denaturation selectivity, and strong activity, which could be applied to a studies, and limited proteolysis, HSL has been shown to be wide range of industrial processes. composed of two domains; an N-terminal binding domain Hormone-sensitive lipase (E.C. 3.1.1.79, HSL) is an and an identical C-terminal catalytic domain [15-17]. The intracellular lipase that can be stimulated by several N-terminal domain has been implicated in mediating hormones, such as catecholamine, adrenocorticotropic protein-protein interactions, whereas the C-terminal domain November 2017 ⎪ Vol. 27⎪ No. 11 1908 T. Doohun Kim harbors a catalytic triad composed of Ser-Asp-His with proteins related to the HSL family have been found, several phosphorylation sites. Specifically, the N-terminal including an esterase from Acinetobacter calcoaceticus, and domain could interact with adipocyte lipid binding protein N-acetyl hydrolases from Streptomyces hygroscopicus [24- [18, 19]. The C-terminal domain has an α/β-hydrolase fold, 26]. Over the last few years, there has been a substantial which has a highly conserved Ser residue in the Gly-x-Ser- increase in the number of publications dealing with the x-Gly sequence [20]. In addition, a regulatory module of isolation and characterization of bHSLs. ~150 amino acids, which is a main target of protein kinase Since the discovery of the bHSL family, many bHSLs A, is located in the C-terminal domain [21]. During have been identified in a wide range of bacteria, such as hydrolysis, this catalytic Ser could work as a nucleophile, Pseudomonas sp. B11-1 [27], Bacillus acidocaldarius [28], oil- which is assisted by the other two residues in close spatial degrading bacterium strain HD-1 [29], Escherichia coli [30], proximity. Archaeoglobus fulgidus [31], Psychrobacter sp. Ant300 [32], Mycobacterium tuberculosis [33-35, 42-44], Streptomyces Bacterial Hormone-Sensitive Lipases coelicolor [36], Oenococcus oeni [37], Rhodococcus sp. CR-53 [38], Rheinheimera sp. [39], Lactobacillus plantarum WCFS1 Besides the highly conserved catalytic motif (Gly-Xaa- [40, 41], and Bacillus halodurans [45]. Furthermore, many Ser-Xaa-Gly) that is observed in most lipases/esterases, the bHSL genes were identified through metagenomic approaches HSL family shows no sequence homology with other directly from environmental DNA samples [46-64]. These previously known mammalian lipases such as pancreatic metagenomic bHSLs were isolated from soil [46, 53, 55, 56], lipase or hepatic lipase [22]. Specifically, the N-terminal mud and sediment-rich water [47], environmental soils domain lacks any similarity with any other known proteins, [48], forest soil [49, 60, 64], marine sediments [50, 51, 58], which is a distinctive feature of HSL. However, several activated sludge [52, 54], mountain soil [57], tidal flat bacterial proteins, which are collectively called bacterial sediment [59], surface sediment [61], and permafrost [62, hormone-sensitive lipases (bHSLs), are homologous to the 63]. Interestingly, bHSL family members were shown to be C-terminal domain of HSL [22]. Initially, lipase 2 of selectively inhibited by 5-methoxy-3-(4-phenoxyphenyl)- Moraxella TA144 was noticed to be homologous to the C- 3H-[1,3,4]oxadiazol-2-one [65]. terminal domain of HSL [22, 23]. Then, other bacterial Although the number of bHSLs being discovered is Fig. 1. Structural organization of human hormone-sensitive lipase (hHSL) and several bacterial HSLs (bHSLs) such as BFAE, Est25, EST2, and AFEST. The hHSL is composed of an N-terminal domain and a C-terminal catalytic domain. The C-terminal domain of hHSL, as well as bHSLs, harbors the catalytic triad (Ser-Asp-His) and conserved motifs (GXSXG, DPXXD, and HGX). J. Microbiol. Biotechnol. Bacterial Hormone-Sensitive Lipases 1909 largely increasing, there is still limited information about from the N-terminal residue and 30-50 residues between this protein family, and only a small number of them have β6 and β7 in the central β-sheet. Specifically, in Est25, the been characterized. The consensus amino acid sequences of first region of the cap domain is composed of 85 amino the representative members of the bHSL family members acids, which form two α-helices that cover the active site are shown in Fig. 1. For biochemical characterizations of [77]. In EST2, this N-terminal region of the cap domain has bHSLs, heterologous expression of the bHSL family been shown to play a significant role in maintaining members were achieved by using E. coli as a host [36-39]. enzyme activity, stability, and specificity [83]. Structural In addition, gene products from uncultured microorganisms comparisons revealed that the most striking differences were successfully expressed and purified [58-61, 63]. The among the bHSL family are in the cap region (Fig. 2). The products of Rv1399c (LipH), Rv3097c (LIPY), (Rv2970 (LipN), main variability resides in the different lengths and relative or Rv1076 (LipU) from M. tuberculosis were overexpressed orientations of helices and connecting loops. In crystal as inclusion bodies, and proteins were refolded with structures of bHSLs, this region has high B factors several modifications [33, 34, 42, 43]. Interestingly, PsyHSL compared with other regions [77-79]. The second region of from Psychrobacter sp. TA144 has been expressed in a the cap domain between β6 and β7 is clearly separated soluble form in the presence of trehalose or benzyl alcohol from the core β-sheets. This region (~150 residues) in the [66]. Moreover, an N-terminally his-tagged Cest-2923 was mammalian HSL family, which is notably longer than that marginally stable in solution, and a C-terminally his-tagged of bHSL proteins, contains several post-translational protein showed an oligomeric conformation suitable for phosphorylation sites for the regulation of these enzymes crystallization [40, 67]. After purification, molecular features
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