Hormone-sensitive lipase is closely related to several bacterial proteins, and distantly related to acetylcholinesterase and lipoprotein lipase: Identification of a superfamily of esterases and lipases

Hemilä, Harri; Koivula, Teija; Palva, Ilkka

doi:10.1016/0005-2760(94)90129-5

Cited by 122 publications

(104 citation statements)

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“…To produce recombinant proteins, Sf21 cells were grown in 150-mm Petri dishes and each 2 ϫ 10 7 cells were infected with 100 l of the high titer recombinant virus; cells were harvested 3 days after infection. To metabolically label HSL, Sf21 cells were grown in complete TNM-FH insect medium supplemented with L- [2,3,4, H]arginine (100 Ci) and L- [4, H]leucine (100 Ci) for 3 days following infection with baculovirus. After harvesting and cell extraction, His-HSL was purified on a Ni-agarose column.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the Functional Interaction of Adipocyte Lipid-binding Protein with Hormone-sensitive Lipase

Shen¹,

Yu²,

Hong³

et al. 2001

Journal of Biological Chemistry

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Hormone-sensitive lipase (HSL)1 is an intracellular neutral lipase that is highly expressed in adipose and steroidogenic tissues (1). The enzyme has broad substrate specificity, displaying hydrolytic activity against triacylglycerol, diacylglycerol, and cholesteryl ester (2). Observations from HSL-null mice have shown that HSL is responsible for ϳ50% of the neutral triglyceride lipase activity and all of the neutral cholesteryl ester hydrolase activity in white adipose tissue (3). Thus, HSL plays an important role in regulating lipolysis and the release of fatty acids from adipose tissue. The sequence of HSL is unrelated to other mammalian lipases, but it shares sequence and structural similarity with several bacterial and fungal lipases (4 -11). This structural similarity is based on the ability to model a large portion of the C-terminal ϳ450 amino acids of HSL as an ␣/␤ hydrolase (7); however, the initial ϳ320 amino acids of the protein share no sequence or structural homology with any known proteins. Within the C-terminal region of the protein lies a 150-amino acid sequence that contains a number of sites phosphorylated in response to lipolytic stimulation (7,12,13). In this regard HSL is unique among lipases for the ability of its activity to be up-regulated by phosphorylation. In addition to phosphorylation, HSL activity appears to be regulated by oligomerization, with the dimeric enzyme exhibiting markedly increased activity (14).Utilizing a yeast two-hybrid screen of a rat adipose tissue library, we previously demonstrated that HSL specifically interacts with adipocyte lipid-binding protein (ALBP or aP2) and identified the N-terminal 300 amino acids of HSL as the region responsible for this interaction (15). ALBP is highly expressed in adipose tissue and is a member of the family of intracellular fatty acid-binding proteins that bind fatty acids, retinoids and other hydrophobic ligands (16). It has been proposed that intracellular fatty acid-binding proteins function to sequester fatty acids, thus serving as an intracellular buffer or participating in facilitating the movement of fatty acids within the cell. In view of our observation that HSL and ALBP interact, we proposed that ALBP might prevent feedback inhibition of HSL by high local concentrations of free fatty acids released at the site of hydrolysis. Consistent with this view, adipocytes from ALBP-null mice exhibit markedly reduced basal and stimulated lipolysis both in situ and in vivo (17,18). In the present studies we have addressed the functional significance of the interaction of HSL with ALBP and provide evidence that the interaction of ALBP with HSL constitutes an additional mechanism whereby the hydrolytic activity of HSL is regulated. Furthermore, we have explored the identification of the sequences in HSL that mediate its interaction with ALBP.

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Section: Methodsmentioning

confidence: 99%

Characterization of the Functional Interaction of Adipocyte Lipid-binding Protein with Hormone-sensitive Lipase

Shen¹,

Yu²,

Hong³

et al. 2001

Journal of Biological Chemistry

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“…A second region of homology was found in the C-terminal part of the protein downstream of the phosphorylation site domain. This region is also found in Moraxella TA144 lipase 2 and other prokaryotic enzymes with a lower similarity (Hemila et al 1994). Therefore, it seems that during the course of evolution regions important for the lipase and/or esterase activity have been conserved whereas the insertion of the regulatory domain of HSL, i.e.…”

Section: G E N O M I C O R G a N I Z A T I O N A N D F U N C T I O N mentioning

confidence: 96%

Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism

1996

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Lipase hormono-sensible de l'adipocyte: un rCgulateur important du mCtabolisme lipidique R E S U M GLe tissu adipeux joue un r81e important dans le contrde de la balance CnergCtique. La mobilisation des triacylglycCrols par la lipase hormono-sensible (EC 3.1.1.3; LHS) est soumis a un contrBle direct par les hormones et neurotransmetteurs qui modulent les concentrations intracellulaires d'AMP cyclique (AMPc). L'hydrolyse des triacylglycCrols par la LHS constitue l'etape limitante de la lipolyse. La LHS est phosphorylCe sur le site rkgulateur (Ser552 dans la LHS humaine) par la p r o t h e kinase dependante de 1'AMPc (EC 2.7.1.37) lorsque les concentrations intracellulaires d' AMPc augmentent. Cette phosphorylation conduit B l'activation de l'enzyme. Une deuxikme site de phosphorylation (Ser5.54 dans la LHS humaine) dCnommC site basal est la cible de la protCine kinase activCe par I'AMP. La phosphorylation du site basal ne conduit pas B l'activation de la LHS et empkche la phosphorylation sur le site regulateur. La phosphorylation et I'activation de la protCine kinase activke par 1'AMP constitue donc un mecanisme antilipolytique qui est fonctionnel sur cellules isolCes mais dont l'importance physiologique n'est pas connue. Les ADN complkmentaires de la LHS de plusieurs espkces ont Ct C clones et la structure des gbnes de LHS de l'homme et de la souris sont connus. Differents domaines fonctionnels de la protCine ont Ct C proposes. Une rCgion d'homologie de sequences en amont de la serine 424 du site catalytique avec cinq enzymes d'organismes procaryotes et une enzyme humaine a ete decrite. La localisation chromosomique du gbne de la LHS est connue chez l'homme (chromosome 19, region q13-1+13.2), le porc et la souris. La mise en evidence de marqueurs polymorphiques dans le g&ne devrait permettre de tester l'hypothkse d'une implication de la LHS dans certaines maladies hereditaires du metabolisme lipidique. L'expression de la LHS varie selon la localisation anatomique du tissu adipeux chez le rat. Cette expression subit Cgalement des variations durant la gestation chez le rat et le cycle annuel chez les mammifbres hibernants. Chez l'homme, les taux d'ARN messagers de la LHS sont diminuCs dans le tissu adipeux de certains patients atteints de cancer. L'activitC enzymatique totale est diminuee chez les patients atteints d'hyperlipidemie familiale combinCe mais pas chez les patients atteints du syndrome metabolique bien que, dans les deux cas, la lipolyse adipocytaire maximale soit diminuke. Les mkcanismes molCculaires de contr6le de l'expression de la LHS sont pratiquement inconnus.

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“…KIAA1363 and its homologs all have the Ser, His and Asp catalytic triad residues, the GDSAG consensus sequence, the HGGG oxyanion hole motif (38) and several other conserved residues. They vary from 310 to 408 amino acids or 35 to 45 kDa (Table 3).…”

Section: Structural Features Of Kiaa1363 Modelmentioning

confidence: 99%

Serine Hydrolase KIAA1363: Toxicological and Structural Features with Emphasis on Organophosphate Interactions

Nomura

Durkin

Chiang

et al. 2006

Chem. Res. Toxicol.

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Serine hydrolase KIAA1363 is highly expressed in invasive cancer cells and is the major protein in mouse brain diethylphosphorylated by and hydrolyzing low levels of chlorpyrifos oxon (CPO) (the activated metabolite of a major insecticide). It is also the primary CPO-hydrolyzing enzyme in spinal cord, kidney, heart, lung, testis and muscle but not liver, a pattern of tissue expression confirmed by fluorophosphonate-rhodamine labeling. KIAA1363-gene deletion using homologous recombination reduces CPO binding, hydrolysis and metabolism 3-to 29-fold on incubation with brain membranes and homogenates determined with 1 nM [ 3 H-ethyl]CPO and the inhibitory potency for residual CPO with butyrylcholinesterase as a biomarker. Studies with knockout mice further show that KIAA1363 partially protects brain AChE and monoacylglycerol lipase from CPO-induced in vivo inhibition. Surprisingly, mouse brain KIAA1363 and AChE are similar in in vitro sensitivity to seven methyl, ethyl and propyl but not higher alkyl OP insecticides and analogs, prompting structural comparisons of the active sites of KIAA1363 and AChE relative to OP potency and selectivity. Homology modeling based largely on the Archaeoglobus fulgidus esterase crystal structure indicates that KIAA1363 has a catalytic triad of S191, D348 and H378, a GDSAG motif and an oxyanion hole of H113, G114, G115 and G116. Excellent selectivity for KIAA1363 is achieved on OP structure optimization with long alkyl chain substituents suggesting that KIAA1363 has larger acyl and leaving group pockets than those of AChE. KIAA1363 reactivates faster than AChE presumably due to differences in the uncoupling of the catalytic triad His upon phosphorylation. The structural modeling of KIAA1363 helps understand OP structure-activity relationships and the toxicological relevance of this detoxifying enzyme.

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Hormone-sensitive lipase is closely related to several bacterial proteins, and distantly related to acetylcholinesterase and lipoprotein lipase: Identification of a superfamily of esterases and lipases

Cited by 122 publications

References 40 publications

Characterization of the Functional Interaction of Adipocyte Lipid-binding Protein with Hormone-sensitive Lipase

Characterization of the Functional Interaction of Adipocyte Lipid-binding Protein with Hormone-sensitive Lipase

Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism

Serine Hydrolase KIAA1363: Toxicological and Structural Features with Emphasis on Organophosphate Interactions

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