Identification of essential aspartic acid and histidine residues of hormone‐sensitive lipase: apparent residues of the catalytic triad

Østerlund, Torben; Contreras, Juan Antonio; Holm, Cecilia

doi:10.1016/s0014-5793(97)00063-x

Cited by 50 publications

(34 citation statements)

References 26 publications

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“…A significant advance in understanding the structure of HSL was made when it was observed that, even in the absence of primary sequence homology, the organization of the secondary structure predicted for the C-terminal ‫ف‬ 450 amino acids of HSL was similar to the secondary structure of acetylcholinesterase and of two fungal lipases from Geotrichum candidum and Candida rugosa (19). Using molecular modeling, it was proposed, and later confirmed by site-directed mutagenesis, that Ser-423, Asp-703, and His-733 (numbered for rat HSL) constitute the catalytic triad for HSL and are found within this C-terminal portion (20). Also located within the C-terminal portion is a 150 amino acid stretch that is not predicted to be composed of ␣ helices or ␤ sheets, but contains known phosphorylation sites and has been termed the regulatory module.…”

Section: Structural and Biochemical Propertiesmentioning

confidence: 56%

Hormone-sensitive lipase

Kraemer

Shen

2002

Journal of Lipid Research

419

125

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Section: Structural and Biochemical Propertiesmentioning

confidence: 56%

Hormone-sensitive lipase

Kraemer

Shen

2002

Journal of Lipid Research

419

125

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“…In fact, it was possible to build a model for the catalytic ␣/␤-hydrolase fold core (11). The proposed residues of the catalytic triad have been probed by site-directed mutagenesis and found to be essential for activity (12,13), strongly supporting the structural model for the catalytic core. In the primary structure, this core is interrupted by approximately 200 residues, including the four phosphorylation sites, which are thought to form a regulatory module (10,11).…”

mentioning

confidence: 71%

Domain Identification of Hormone-sensitive Lipase by Circular Dichroism and Fluorescence Spectroscopy, Limited Proteolysis, and Mass Spectrometry

Østerlund¹,

Beussman²,

Julenius³

et al. 1999

Journal of Biological Chemistry

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To analyze the structural domain composition of HSL in more detail, we applied biophysical methods. Denaturation of HSL was followed by circular dichroism measurements and fluorescence spectroscopy, revealing that the unfolding of HSL is a two-step event. Using limited proteolysis in combination with mass spectrometry, several proteolytic fragments of HSL were identified, including one corresponding exactly to the proposed N-terminal domain. Major cleavage sites were found in the predicted hinge region between the two domains and in the regulatory module of the C-terminal, catalytic domain. Analyses of a hinge region cleavage mutant and calculations of the hydropathic pattern of HSL further suggest that the hinge region and regulatory module are exposed parts of HSL. Together, these data support our previous hypothesis that HSL consists of two major structural domains, encoded by exons 1-4 and 5-9, respectively, of which the latter contains an exposed regulatory module outside the catalytic ␣/␤-hydrolase fold core.

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“…Multiple potential transcription factor binding elements upstream of each transcriptional start site suggest the possibility of differential transcriptional regulation of HSL in different tissues and under various physiological conditions. According to the HSL domain structure model [the three-dimensional (3D) structure of the enzyme remains to be elucidated], the enzyme can be subdivided into three functional regions (41)(42)(43)(44). The N-terminal domain (amino acids 1-300) is believed to mediate enzyme dimerization (45) and interaction with FABP4, a fatty acid binding protein known to enhance HSL enzyme activity (46)(47)(48).…”

Section: Hsl Enzymologymentioning

confidence: 99%

Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores

Zechner

Kienesberger

Haemmerle

et al. 2009

Journal of Lipid Research

477

377

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Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL-and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzymeʼs activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the "lipolysome," a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL.-Zechner, R., P. C. Kienesberger, G. Haemmerle, R. Zimmermann, and A. Lass. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J. Lipid Res. 2009. 50: 3-21.Supplementary key words lipolysis • hydrolase • neutral lipid storage disease Lipid homeostasis reflects a balance of processes, designed to generate fatty acids (FAs) and lipids, deliver them from their site of origin to target tissues, and catabolize them for metabolic purposes. Innumerable genes and signal components are responsible for an integrated communication network between many tissues and organs, including adipose tissue, liver, muscles, the digestive tract, pancreas, and the nervous system. This network ultimately accounts for the accurate regulation of lipid and energy homeostasis. Despite the central physiological importance of these processes for human health, many basic mechanisms regulating the synthesis, uptake, storage, and utilization of lipids remain insufficiently characterized.FAs are vital components of essentially all known organisms. They are important substrates for oxidation and the production of cellular energy. FAs are essential precursors for all lipid classes, including those forming biological membranes. Finally, they are important for protein function in acylated proteins and as ligands for nuclear receptor transcription factors. In contrast to these "beneficial" characteristics, unesterified FAs can become deleterious for cells when present even at relatively low concentrations. The chronic exposure of nona...

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Identification of essential aspartic acid and histidine residues of hormone‐sensitive lipase: apparent residues of the catalytic triad

Cited by 50 publications

References 26 publications

Hormone-sensitive lipase

Hormone-sensitive lipase

Domain Identification of Hormone-sensitive Lipase by Circular Dichroism and Fluorescence Spectroscopy, Limited Proteolysis, and Mass Spectrometry

Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores

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