Breinbauer R

References (18)

Title : Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes - Grabner_2022_J.Am.Chem.Soc__
Author(s) : Grabner GF , Guttenberger N , Mayer N , Migglautsch-Sulzer AK , Lembacher-Fadum C , Fawzy N , Bulfon D , Hofer P , Zullig T , Hartig L , Kulminskaya N , Chalhoub G , Schratter M , Radner FPW , Preiss-Landl K , Masser S , Lass A , Zechner R , Gruber K , Oberer M , Breinbauer R , Zimmermann R
Ref : Journal of the American Chemical Society , : , 2022
Abstract : Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme-inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.
ESTHER : Grabner_2022_J.Am.Chem.Soc__
PubMedSearch : Grabner_2022_J.Am.Chem.Soc__
PubMedID: 35362954

Title : Structural Changes in the Cap of Rv0183\/mtbMGL Modulate the Shape of the Binding Pocket - Grininger_2021_Biomolecules_11_1299
Author(s) : Grininger C , Leypold M , Aschauer P , Pavkov-Keller T , Riegler-Berket L , Breinbauer R , Oberer M
Ref : Biomolecules , 11 :1299 , 2021
Abstract : doi:10.3390/biom11091299 Tuberculosis continues to be a major threat to the human population. Global efforts to eradicate the disease are ongoing but are hampered by the increasing occurrence of multidrug-resistant strains of Mycobacterium tuberculosis. Therefore, the development of new treatment, and the exploration of new druggable targets and treatment strategies, are of high importance. Rv0183/mtbMGL, is a monoacylglycerol lipase of M. tuberculosis and it is involved in providing fatty acids and glycerol as building blocks and as an energy source. Since the lipase is expressed during the dormant and active phase of an infection, Rv0183/mtbMGL is an interesting target for inhibition. In this work, we determined the crystal structures of a surface-entropy reduced variant K74A Rv0183/mtbMGL in its free form and in complex with a substrate mimicking inhibitor. The two structures reveal conformational changes in the cap region that forms a major part of the substrate/inhibitor binding region. We present a completely closed conformation in the free form and semi-closed conformation in the ligand-bound form. These conformations differ from the previously published, completely open conformation of Rv0183/mtbMGL. Thus, this work demonstrates the high conformational plasticity of the cap from open to closed conformations and provides useful insights into changes in the substrate-binding pocket, the target of potential small-molecule inhibitors.
ESTHER : Grininger_2021_Biomolecules_11_1299
PubMedSearch : Grininger_2021_Biomolecules_11_1299
PubMedID: 34572512
Gene_locus related to this paper: myctu-rv0183

Title : Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL) - Mayer_2020_Bioorg.Med.Chem_28_115610
Author(s) : Mayer N , Schweiger M , Fuchs E , Migglautsch AK , Doler C , Grabner GF , Romauch M , Melcher MC , Zechner R , Zimmermann R , Breinbauer R
Ref : Bioorganic & Medicinal Chemistry , 28 :115610 , 2020
Abstract : High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.
ESTHER : Mayer_2020_Bioorg.Med.Chem_28_115610
PubMedSearch : Mayer_2020_Bioorg.Med.Chem_28_115610
PubMedID: 32690265

Title : Metabolic disease and ABHD6 alter the circulating bis(monoacylglycerol)phosphate profile in mice and humans - Grabner_2019_J.Lipid.Res_60_1020
Author(s) : Grabner GF , Fawzy N , Pribasnig MA , Trieb M , Taschler U , Holzer M , Schweiger M , Wolinski H , Kolb D , Horvath A , Breinbauer R , Rulicke T , Rabl R , Lass A , Stadlbauer V , Hutter-Paier B , Stauber RE , Fickert P , Zechner R , Marsche G , Eichmann TO , Zimmermann R
Ref : J Lipid Res , 60 :1020 , 2019
Abstract : Bis(monoacylglycerol)phosphate (BMP) is a phospholipid that is crucial for lipid degradation and sorting in acidic organelles. Genetic and drug-induced lysosomal storage disorders (LSDs) are associated with increased BMP concentrations in tissues and in the circulation. Data on BMP in disorders other than LSDs, however, are scarce, and key enzymes regulating BMP metabolism remain elusive. Here, we demonstrate that common metabolic disorders and the intracellular BMP hydrolase alpha/beta-hydrolase domain-containing 6 (ABHD6) affect BMP metabolism in mice and humans. In mice, dietary lipid overload strongly affects BMP concentration and FA composition in the liver and plasma, similar to what has been observed in LSDs. Notably, distinct changes in the BMP FA profile enable a clear distinction between lipid overload and drug-induced LSDs. Global deletion of ABHD6 increases circulating BMP concentrations but does not cause LSDs. In humans, nonalcoholic fatty liver disease and liver cirrhosis affect the serum BMP FA composition and concentration. Furthermore, we identified a patient with a loss-of-function mutation in the ABHD6 gene, leading to an altered circulating BMP profile. In conclusion, our results suggest that common metabolic diseases and ABHD6 affect BMP metabolism in mice and humans.
ESTHER : Grabner_2019_J.Lipid.Res_60_1020
PubMedSearch : Grabner_2019_J.Lipid.Res_60_1020
PubMedID: 30894461
Gene_locus related to this paper: human-ABHD6

Title : The crystal structure of monoacylglycerol lipase from M. tuberculosis reveals the basis for specific inhibition - Aschauer_2018_Sci.Rep_8_8948
Author(s) : Aschauer P , Zimmermann R , Breinbauer R , Pavkov-Keller T , Oberer M
Ref : Sci Rep , 8 :8948 , 2018
Abstract : Monoacylglycerol lipases (MGLs) are enzymes that hydrolyze monoacylglycerol into a free fatty acid and glycerol. Fatty acids can be used for triacylglycerol synthesis, as energy source, as building blocks for energy storage, and as precursor for membrane phospholipids. In Mycobacterium tuberculosis, fatty acids also serve as precursor for polyketide lipids like mycolic acids, major components of the cellular envelope associated to resistance for drug. We present the crystal structure of the MGL Rv0183 from Mycobacterium tuberculosis (mtbMGL) in open conformation. The structure reveals remarkable similarities with MGL from humans (hMGL) in both, the cap region and the alpha/beta core. Nevertheless, mtbMGL could not be inhibited with JZL-184, a known inhibitor of hMGL. Docking studies provide an explanation why the activity of mtbMGL was not affected by the inhibitor. Our findings suggest that specific inhibition of mtbMGL from Mycobacterium tuberculosis, one of the oldest recognized pathogens, is possible without influencing hMGL.
ESTHER : Aschauer_2018_Sci.Rep_8_8948
PubMedSearch : Aschauer_2018_Sci.Rep_8_8948
PubMedID: 29895832
Gene_locus related to this paper: myctu-rv0183

Title : Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice - Schweiger_2017_Nat.Commun_8_14859
Author(s) : Schweiger M , Romauch M , Schreiber R , Grabner GF , Hutter S , Kotzbeck P , Benedikt P , Eichmann TO , Yamada S , Knittelfelder O , Diwoky C , Doler C , Mayer N , De Cecco W , Breinbauer R , Zimmermann R , Zechner R
Ref : Nat Commun , 8 :14859 , 2017
Abstract : Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.
ESTHER : Schweiger_2017_Nat.Commun_8_14859
PubMedSearch : Schweiger_2017_Nat.Commun_8_14859
PubMedID: 28327588

Title : Enzymatic hydrolysis of poly(ethylene furanoate) - Pellis_2016_J.Biotechnol_235_47
Author(s) : Pellis A , Haernvall K , Pichler CM , Ghazaryan G , Breinbauer R , Guebitz GM
Ref : J Biotechnol , 235 :47 , 2016
Abstract : The urgency of producing new environmentally-friendly polyesters strongly enhanced the development of bio-based poly(ethylene furanoate) (PEF) as an alternative to plastics like poly(ethylene terephthalate) (PET) for applications that include food packaging, personal and home care containers and thermoforming equipment. In this study, PEF powders of various molecular weights (6, 10 and 40kDa) were synthetized and their susceptibility to enzymatic hydrolysis was investigated for the first time. According to LC/TOF-MS analysis, cutinase 1 from Thermobifida cellulosilytica liberated both 2,5-furandicarboxylic acid and oligomers of up to DP4. The enzyme preferentially hydrolyzed PEF with higher molecular weights but was active on all tested substrates. Mild enzymatic hydrolysis of PEF has a potential both for surface functionalization and monomers recycling.
ESTHER : Pellis_2016_J.Biotechnol_235_47
PubMedSearch : Pellis_2016_J.Biotechnol_235_47
PubMedID: 26854948
Gene_locus related to this paper: thefu-q6a0i4

Title : Crystal structure of the Saccharomyces cerevisiae monoglyceride lipase Yju3p - Aschauer_2016_Biochim.Biophys.Acta_1861_462
Author(s) : Aschauer P , Rengachari S , Lichtenegger J , Schittmayer M , Das KM , Mayer N , Breinbauer R , Birner-Gruenberger R , Gruber CC , Zimmermann R , Gruber K , Oberer M
Ref : Biochimica & Biophysica Acta , 1861 :462 , 2016
Abstract : Monoglyceride lipases (MGLs) are a group of alpha/beta-hydrolases that catalyze the hydrolysis of monoglycerides (MGs) into free fatty acids and glycerol. This reaction serves different physiological functions, namely in the last step of phospholipid and triglyceride degradation, in mammalian endocannabinoid and arachidonic acid metabolism, and in detoxification processes in microbes. Previous crystal structures of MGLs from humans and bacteria revealed conformational plasticity in the cap region of this protein and gave insight into substrate binding. In this study, we present the structure of a MGL from Saccharomyces cerevisiae called Yju3p in its free form and in complex with a covalently bound substrate analog mimicking the tetrahedral intermediate of MG hydrolysis. These structures reveal a high conservation of the overall shape of the MGL cap region and also provide evidence for conformational changes in the cap of Yju3p. The complex structure reveals that, despite the high structural similarity, Yju3p seems to have an additional opening to the substrate binding pocket at a different position compared to human and bacterial MGL. Substrate specificities towards MGs with saturated and unsaturated alkyl chains of different lengths were tested and revealed highest activity towards MG containing a C18:1 fatty acid.
ESTHER : Aschauer_2016_Biochim.Biophys.Acta_1861_462
PubMedSearch : Aschauer_2016_Biochim.Biophys.Acta_1861_462
PubMedID: 26869448
Gene_locus related to this paper: yeast-mgll

Title : Biocatalyzed approach for the surface functionalization of poly(L-lactic acid) films using hydrolytic enzymes - Pellis_2015_Biotechnol.J_10_1739
Author(s) : Pellis A , Herrero Acero E , Weber H , Obersriebnig M , Breinbauer R , Srebotnik E , Guebitz GM
Ref : Biotechnol J , 10 :1739 , 2015
Abstract : Poly(lactic acid) as a biodegradable thermoplastic polyester has received increasing attention. This renewable polyester has found applications in a wide range of products such as food packaging, textiles and biomedical devices. Its major drawbacks are poor toughness, slow degradation rate and lack of reactive side-chain groups. An enzymatic process for the grafting of carboxylic acids onto the surface of poly(L-lactic acid) (PLLA) films was developed using Candida antarctica lipase B as a catalyst. Enzymatic hydrolysis of the PLLA film using Humicola insolens cutinase in order to increase the number of hydroxyl and carboxylic groups on the outer polymer chains for grafting was also assessed and showed a change of water contact angle from 74.6 to 33.1 degrees while the roughness and waviness were an order of magnitude higher in comparison to the blank. Surface functionalization was demonstrated using two different techniques, (14) C-radiochemical analysis and X-ray photoelectron spectroscopy (XPS) using (14) C-butyric acid sodium salt and 4,4,4-trifluorobutyric acid as model molecules, respectively. XPS analysis showed that 4,4,4-trifluorobutyric acid was enzymatically coupled based on an increase of the fluor content from 0.19 to 0.40%. The presented (14) C-radiochemical analyses are consistent with the XPS data indicating the potential of enzymatic functionalization in different reaction conditions.
ESTHER : Pellis_2015_Biotechnol.J_10_1739
PubMedSearch : Pellis_2015_Biotechnol.J_10_1739
PubMedID: 25963883

Title : Adipose triglyceride lipase is involved in the mobilization of triglyceride and retinoid stores of hepatic stellate cells - Taschler_2015_Biochim.Biophys.Acta_1851_937
Author(s) : Taschler U , Schreiber R , Chitraju C , Grabner GF , Romauch M , Wolinski H , Haemmerle G , Breinbauer R , Zechner R , Lass A , Zimmermann R
Ref : Biochimica & Biophysica Acta , 1851 :937 , 2015
Abstract : Hepatic stellate cells (HSCs) store triglycerides (TGs) and retinyl ester (RE) in cytosolic lipid droplets. RE stores are degraded following retinoid starvation or in response to pathogenic stimuli resulting in HSC activation. At present, the major enzymes catalyzing lipid degradation in HSCs are unknown. In this study, we investigated whether adipose triglyceride lipase (ATGL) is involved in RE catabolism of HSCs. Additionally, we compared the effects of ATGL deficiency and hormone-sensitive lipase (HSL) deficiency, a known RE hydrolase (REH), on RE stores in liver and adipose tissue. We show that ATGL degrades RE even in the presence of TGs, implicating that these substrates compete for ATGL binding. REH activity was stimulated and inhibited by comparative gene identification-58 and G0/G1 switch gene-2, respectively, the physiological regulators of ATGL activity. In cultured primary murine HSCs, pharmacological inhibition of ATGL, but not HSL, increased RE accumulation. In mice globally lacking ATGL or HSL, RE contents in white adipose tissue were decreased or increased, respectively, while plasma retinol and liver RE levels remained unchanged. In conclusion, our study shows that ATGL acts as REH in HSCs promoting the degradation of RE stores in addition to its established function as TG lipase. HSL is the predominant REH in adipocytes but does not affect lipid mobilization in HSCs.
ESTHER : Taschler_2015_Biochim.Biophys.Acta_1851_937
PubMedSearch : Taschler_2015_Biochim.Biophys.Acta_1851_937
PubMedID: 25732851

Title : alpha\/beta Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal\/Lysosomal Lipid Bis(monoacylglycero)phosphate - Pribasnig_2015_J.Biol.Chem_290_29869
Author(s) : Pribasnig MA , Mrak I , Grabner GF , Taschler U , Knittelfelder O , Scherz B , Eichmann TO , Heier C , Grumet L , Kowaliuk J , Romauch M , Holler S , Anderl F , Wolinski H , Lass A , Breinbauer R , Marsche G , Brown JM , Zimmermann R
Ref : Journal of Biological Chemistry , 290 :29869 , 2015
Abstract : alpha/beta Hydrolase domain-containing 6 (ABHD6) can act as monoacylglycerol hydrolase and is believed to play a role in endocannabinoid signaling as well as in the pathogenesis of obesity and liver steatosis. However, the mechanistic link between gene function and disease is incompletely understood. Here we aimed to further characterize the role of ABHD6 in lipid metabolism. We show that mouse and human ABHD6 degrade bis(monoacylglycero)phosphate (BMP) with high specific activity. BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes/lysosomes, where it plays a key role in the formation of intraluminal vesicles and in lipid sorting. Up to now, little has been known about the catabolism of this lipid. Our data demonstrate that ABHD6 is responsible for approximately 90% of the BMP hydrolase activity detected in the liver and that knockdown of ABHD6 increases hepatic BMP levels. Tissue fractionation and live-cell imaging experiments revealed that ABHD6 co-localizes with late endosomes/lysosomes. The enzyme is active at cytosolic pH and lacks acid hydrolase activity, implying that it degrades BMP exported from acidic organelles or de novo-formed BMP. In conclusion, our data suggest that ABHD6 controls BMP catabolism and is therefore part of the late endosomal/lysosomal lipid-sorting machinery.
ESTHER : Pribasnig_2015_J.Biol.Chem_290_29869
PubMedSearch : Pribasnig_2015_J.Biol.Chem_290_29869
PubMedID: 26491015
Gene_locus related to this paper: human-ABHD6

Title : Weighing the proteasome for covalent modifications - Birner-Gruenberger_2015_Chem.Biol_22_315
Author(s) : Birner-Gruenberger R , Breinbauer R
Ref : Chemical Biology , 22 :315 , 2015
Abstract : Posttranslational modifications (PTMs) control protein function, but established peptide-based proteomic methods often fail to provide a comprehensive view of PTMs. In this issue of Chemistry & Biology, Gersch et al. describe an efficient combination of chromatographic separation and top-down mass spectrometry that together with an intuitive visualization tool allowed them to screen the proteasome for PTMs and covalently binding inhibitors.
ESTHER : Birner-Gruenberger_2015_Chem.Biol_22_315
PubMedSearch : Birner-Gruenberger_2015_Chem.Biol_22_315
PubMedID: 25794435

Title : A robust and simple protocol for the synthesis of arylfluorophosphonates - Leypold_2015_Tetrahedron.Lett_56_5619
Author(s) : Leypold M , Wallace PW , Kljajic M , Schittmayer M , Pletz J , Illaszewicz-Trattner C , Guebitz GM , Birner-Gruenberger R , Breinbauer R
Ref : Tetrahedron Letters , 56 :5619 , 2015
Abstract : Abstract: Fluorophosphonates represent powerful probes for the identification and analysis of active serine hydrolases in activity based protein profiling. Although alkylphosphonofluoridates are widely used for such purposes, little is known about the synthesis and purification of arylphosphonofluoridates, which may be useful tools for screening enzyme activities toward aromatic esters. Our optimized route makes this subclass of transition state inhibitors broadly accessible for a diverse series of phosphonic acid derivatives using a combination of selective monoesterification with EDC.HCl and subsequent mild fluorination with DAST. All compounds were isolated as pure materials using a simple acid-base extraction protocol in 7693% yields over two steps. These probes can be stored under an inert atmosphere at -24C for several months without significant degradation.
ESTHER : Leypold_2015_Tetrahedron.Lett_56_5619
PubMedSearch : Leypold_2015_Tetrahedron.Lett_56_5619

Title : Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL) - Mayer_2015_Bioorg.Med.Chem_23_2904
Author(s) : Mayer N , Schweiger M , Melcher MC , Fledelius C , Zechner R , Zimmermann R , Breinbauer R
Ref : Bioorganic & Medicinal Chemistry , 23 :2904 , 2015
Abstract : Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50=10muM in an assay with COS7-cell lysate overexpressing murine ATGL.
ESTHER : Mayer_2015_Bioorg.Med.Chem_23_2904
PubMedSearch : Mayer_2015_Bioorg.Med.Chem_23_2904
PubMedID: 25778769

Title : Fatty Acid-binding Proteins Interact with Comparative Gene Identification-58 Linking Lipolysis with Lipid Ligand Shuttling - Hofer_2015_J.Biol.Chem_290_18438
Author(s) : Hofer P , Boeszoermenyi A , Jaeger D , Feiler U , Arthanari H , Mayer N , Zehender F , Rechberger G , Oberer M , Zimmermann R , Lass A , Haemmerle G , Breinbauer R , Zechner R , Preiss-Landl K
Ref : Journal of Biological Chemistry , 290 :18438 , 2015
Abstract : The coordinated breakdown of intracellular triglyceride (TG) stores requires the exquisitely regulated interaction of lipolytic enzymes with regulatory, accessory, and scaffolding proteins. Together they form a dynamic multiprotein network designated as the "lipolysome." Adipose triglyceride lipase (Atgl) catalyzes the initiating step of TG hydrolysis and requires comparative gene identification-58 (Cgi-58) as a potent activator of enzyme activity. Here, we identify adipocyte-type fatty acid-binding protein (A-Fabp) and other members of the fatty acid-binding protein (Fabp) family as interaction partners of Cgi-58. Co-immunoprecipitation, microscale thermophoresis, and solid phase assays proved direct protein/protein interaction between A-Fabp and Cgi-58. Using nuclear magnetic resonance titration experiments and site-directed mutagenesis, we located a potential contact region on A-Fabp. In functional terms, A-Fabp stimulates Atgl-catalyzed TG hydrolysis in a Cgi-58-dependent manner. Additionally, transcriptional transactivation assays with a luciferase reporter system revealed that Fabps enhance the ability of Atgl/Cgi-58-mediated lipolysis to induce the activity of peroxisome proliferator-activated receptors. Our studies identify Fabps as crucial structural and functional components of the lipolysome.
ESTHER : Hofer_2015_J.Biol.Chem_290_18438
PubMedSearch : Hofer_2015_J.Biol.Chem_290_18438
PubMedID: 25953897
Gene_locus related to this paper: human-ABHD5

Title : Conformational plasticity and ligand binding of bacterial monoacylglycerol lipase - Rengachari_2013_J.Biol.Chem_288_31093
Author(s) : Rengachari S , Aschauer P , Schittmayer M , Mayer N , Gruber K , Breinbauer R , Birner-Gruenberger R , Dreveny I , Oberer M
Ref : Journal of Biological Chemistry , 288 :31093 , 2013
Abstract : Monoacylglycerol lipases (MGLs) play an important role in lipid catabolism across all kingdoms of life by catalyzing the release of free fatty acids from monoacylglycerols. The three-dimensional structures of human and a bacterial MGL were determined only recently as the first members of this lipase family. In addition to the alpha/beta-hydrolase core, they showed unexpected structural similarities even in the cap region. Nevertheless, the structural basis for substrate binding and conformational changes of MGLs is poorly understood. Here, we present a comprehensive study of five crystal structures of MGL from Bacillus sp. H257 in its free form and in complex with different substrate analogs and the natural substrate 1-lauroylglycerol. The occurrence of different conformations reveals a high degree of conformational plasticity of the cap region. We identify a specific residue, Ile-145, that might act as a gatekeeper restricting access to the binding site. Site-directed mutagenesis of Ile-145 leads to significantly reduced hydrolase activity. Bacterial MGLs in complex with 1-lauroylglycerol, myristoyl, palmitoyl, and stearoyl substrate analogs enable identification of the binding sites for the alkyl chain and the glycerol moiety of the natural ligand. They also provide snapshots of the hydrolytic reaction of a bacterial MGL at different stages. The alkyl chains are buried in a hydrophobic tunnel in an extended conformation. Binding of the glycerol moiety is mediated via Glu-156 and water molecules. Analysis of the structural features responsible for cap plasticity and the binding modes of the ligands suggests conservation of these features also in human MGL.
ESTHER : Rengachari_2013_J.Biol.Chem_288_31093
PubMedSearch : Rengachari_2013_J.Biol.Chem_288_31093
PubMedID: 24014019
Gene_locus related to this paper: bac25-mglp

Title : Development of small-molecule inhibitors targeting adipose triglyceride lipase - Mayer_2013_Nat.Chem.Biol_9_785
Author(s) : Mayer N , Schweiger M , Romauch M , Grabner GF , Eichmann TO , Fuchs E , Ivkovic J , Heier C , Mrak I , Lass A , Hofler G , Fledelius C , Zechner R , Zimmermann R , Breinbauer R
Ref : Nat Chemical Biology , 9 :785 , 2013
Abstract : Adipose triglyceride lipase (ATGL) is rate limiting in the mobilization of fatty acids from cellular triglyceride stores. This central role in lipolysis marks ATGL as an interesting pharmacological target as deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Here we report on the development and characterization of a small-molecule inhibitor of ATGL. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo.
ESTHER : Mayer_2013_Nat.Chem.Biol_9_785
PubMedSearch : Mayer_2013_Nat.Chem.Biol_9_785
PubMedID: 24096302

Title : Protein structure similarity as guiding principle for combinatorial library design - Koch_2003_Biol.Chem_384_1265
Author(s) : Koch MA , Breinbauer R , Waldmann H
Ref : Biol Chem , 384 :1265 , 2003
Abstract : Proteins are modularly built from a limited set of approximately 1000 structural domains. The evolutionary relationship within a domain family suggests that the knowledge about a common fold structure can be exploited for the design of small molecule libraries in the development of inhibitors and ligands. This principle has been used for the synthesis of inhibitors for kinases sharing the same fold. It can also be applied for proteins which share the same fold architecture yet belong to different functional classes. Bestatin--originally known as an aminopeptidase inhibitor--was employed as guiding structure for the development of leukotriene A4 hydrolase inhibitors. A combinatorial approach helped to identify inhibitors for sulfotransferases which share structural similarity with nucleotide kinases using a kinase inhibitor core structure as guiding principle.
ESTHER : Koch_2003_Biol.Chem_384_1265
PubMedSearch : Koch_2003_Biol.Chem_384_1265
PubMedID: 14515987