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<StructureSection load='1akn' size='400' side='right' caption='Structure of Pancreatic Lipase (PDB entry [[1akn]])' scene=''>
<StructureSection load='1akn' size='300' side='right' caption='Structure of glycosylated pancreatic lipase (PDB entry [[1akn]])' scene=''>
{{TOC limit|limit=2}}
{{TOC limit|limit=2}}


== '''Introduction''' ==
== '''Introduction''' ==
'''Lipase''' catalyzes the breakdown of lipids by hydrolyzing the esters of fatty acids.  Its function is important for digestion and promoting absorption of fats in the intestines.  Lipase is primarily found in and secreted by the pancreas, but is also found in the saliva and stomach. Pancreatic lipase (PDB ID:  [[1hpl]]) which is pictured to the right, is a carboxylic ester hydrolase.  It is also commonly called pancreatic triacylglycerol lipase and its enzyme class number is E.C. 3.1.1.3 <ref name="1HPL PDB SUM">[http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1hpl&template=main.html] 1HPL PDB SUM </ref>.  The bile salt-stimulated lipase (BSSL) is found in breast milk.  The hormone-sensitive lipase (LIPE) hydrolyzes a variety of esters.  Monoacylglycerol lipase (MAGL) hydrolyzes intracellular triglycerides to fatty acid and glycerol.  MAGL functions together with LIPE.  The reaction catalyzed by the enzyme is shown below.
'''Lipase''' catalyzes the breakdown of lipids by hydrolyzing the esters of fatty acids.  Its function is important for digestion and promoting absorption of fats in the intestines.  Lipase is primarily found in and secreted by the pancreas, but is also found in the saliva and stomach.<br />
* '''Pancreatic lipase''' (PDB ID:  [[1hpl]]) which is pictured to the right, is a carboxylic ester hydrolase.  It is also commonly called '''pancreatic triacylglycerol lipase''' and its enzyme class number is E.C. 3.1.1.3 <ref name="1HPL PDB SUM">[http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1hpl&template=main.html] 1HPL PDB SUM </ref>.<br />
* The '''bile salt-stimulated lipase''' (BSSL) is found in breast milk.<br />
* The '''hormone-sensitive lipase''' (LIPE) hydrolyzes a variety of esters.  For details see [[Hormone sensitive lipase]].<br />
*  '''Monoacylglycerol lipase''' (MAGL) hydrolyzes intracellular triglycerides to fatty acid and glycerol.  MAGL functions together with LIPE.  For details see [[Monoglyceride lipase]].
 
The reaction catalyzed by the enzyme is shown below.  


[[Image:Picture 1.png]]   
[[Image:Picture 1.png]]   
Further breakdown ultimately results in 2-monoacylglycerols and free fatty acids <ref name= "A cross-linked complex between horse pancreatic lipase and colipase">[http://www.sciencedirect.com/science/article/pii/0014579389815923] A cross-linked complex between horse pancreatic lipase and colipase</ref>. An in depth discussion of the mechanism can be found in the Lipase Catalytic Mechanism section. The determination of the structure and function of lipase was a gradual process.  Lipase activity was first demonstrated in the pancreas by Claude Bernard in 1846.  However, it wasn't until 1955 that Mattson and Beck demonstrated a high-specificity of pancreatic lipase for triglyceride primary esters <ref name= "History of Lipids">[http://www.cyberlipid.org/history/history1.htm] History of Lipids</ref>.  In recent years, determination of the crystal structure of pancreatic lipase has become the primary focus as many scientists have worked to further this.<br />
Further breakdown ultimately results in 2-monoacylglycerols and free fatty acids <ref name= "A cross-linked complex between horse pancreatic lipase and colipase">[http://www.sciencedirect.com/science/article/pii/0014579389815923] A cross-linked complex between horse pancreatic lipase and colipase</ref>. An in depth discussion of the mechanism can be found in the Lipase Catalytic Mechanism section. The determination of the structure and function of lipase was a gradual process.  Lipase activity was first demonstrated in the pancreas by Claude Bernard in 1846.  However, it wasn't until 1955 that Mattson and Beck demonstrated a high-specificity of pancreatic lipase for triglyceride primary esters <ref name= "History of Lipids">[http://www.cyberlipid.org/history/history1.htm] History of Lipids</ref>.  In recent years, determination of the crystal structure of pancreatic lipase has become the primary focus as many scientists have worked to further this.<br />
=='''See also'''==<br />
 
==See also==
* [[Molecular Playground/Pancreatic Lipase]]<br />
* [[Molecular Playground/Pancreatic Lipase]]<br />
* [[Lipase lid morph]]<br />
* [[Lipase lid morph]]<br />
* [[Hormone sensitive lipase]]<br />
* [[Hormone sensitive lipase]]<br />
* [[Lipase from Candida antarctica in closed state]]
* [[Lipase from Candida antarctica in closed state]]<br />
* [[Monoglyceride lipase]]
* [[Monoglyceride lipase]]<br />
* [[Human gastric lipase]]<br />
* [[Lipoprotein Lipase (LPL) complexed with GPIHBP1]]<br />
* [[Lipase (Hebrew)]]<br />
* [[Lipid metabolism]]


== '''Structure''' ==
== '''Structure''' ==
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The carbonyl reforms with the glycerol backbone segment acting as the leaving group (Reaction 2).   
The carbonyl reforms with the glycerol backbone segment acting as the leaving group (Reaction 2).   


[[Image:M0218.stg02.gif|center|]]
[[Image:M0218.stg02r.gif|center|]]
A water molecule then donates a proton to the histidine, creating a reactive hydroxyl anion. The hydroxyl anion can then attack the carbonyl carbon of the lipid, forming another negatively charged tetrahedral intermediate which is stabilized in the oxyanion hole (Reaction 3).   
A water molecule then donates a proton to the histidine, creating a reactive hydroxyl anion. The hydroxyl anion can then attack the carbonyl carbon of the lipid, forming another negatively charged tetrahedral intermediate which is stabilized in the oxyanion hole (Reaction 3).   


[[Image:M0218.stg03.gif|center|]]
[[Image:M0218.stg03r.gif|center|]]
Upon reformation of the carbonyl, the catalytic serine is released and monoglyceride and fatty acid monomers diffuse away (Reaction 4).   
Upon reformation of the carbonyl, the catalytic serine is released and monoglyceride and fatty acid monomers diffuse away (Reaction 4).   


[[Image:M0218.stg04.gif|center|]]
[[Image:M0218.stg04r.gif|center|]]


== '''Inhibition of Pancreatic Lipase''' ==
== '''Inhibition of Pancreatic Lipase''' ==
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== '''Clinical Significance''' ==
== '''Clinical Significance''' ==
Pancreatic lipase is secreted into the duodenum through the duct system of the pancreas. In a healthy individual, it is at very low concentration in serum. Under extreme disruption of pancreatic function, such as pancreatitis or pancreatic cancer, the pancreas may begin to digest itself and release pancreatic enzymes including pancreatic lipase into serum. Measurement of serum concentration of pancreatic lipase can therefore aid in diagnosis of acute pancreatitis.<ref>"Pancreatic lipase". Wikipedia: The Free Encyclopedia. 7 Nov 2011 [http://en.wikipedia.org/wiki/Pancreatic_lipase]</ref>.  Due to lipase's activity in the digestion and absorption of fat, there has been a growing market for lipase inhibitors for weight loss pharmaceuticals.  The most popular is Orlistat (or Xenical®) which is a natural product from ''Streptomyces toxytricini'' and is the hydrogenation product of lipostation- an irreversible lipase inhibitor.  This inhibitor also acts by binding Ser152, producing an ester which hydrolyzes so slow that it is practically irreversible <ref>Kordik, C., Reitz, A. "Pharmacological Treatment of Obesity: Therapeutic Strategies" Journal of Medicinal Chemistry, 1999 (42).</ref>.
Pancreatic lipase is secreted into the duodenum through the duct system of the pancreas. In a healthy individual, it is at very low concentration in serum. Under extreme disruption of pancreatic function, such as pancreatitis or pancreatic cancer, the pancreas may begin to digest itself and release pancreatic enzymes including pancreatic lipase into serum. Measurement of serum concentration of pancreatic lipase can therefore aid in diagnosis of acute pancreatitis.<ref>"Pancreatic lipase". Wikipedia: The Free Encyclopedia. 7 Nov 2011 [http://en.wikipedia.org/wiki/Pancreatic_lipase]</ref>.  Due to lipase's activity in the digestion and absorption of fat, there has been a growing market for lipase inhibitors for weight loss pharmaceuticals.  The most popular is Orlistat (or Xenical®) which is a natural product from ''Streptomyces toxytricini'' and is the hydrogenation product of lipostation- an irreversible lipase inhibitor.  This inhibitor also acts by binding Ser152, producing an ester which hydrolyzes so slow that it is practically irreversible <ref>Kordik, C., Reitz, A. "Pharmacological Treatment of Obesity: Therapeutic Strategies" Journal of Medicinal Chemistry, 1999 (42).</ref>.
</StructureSection>


== 3D Structures of Lipase ==
== 3D Structures of Lipase ==
[[Lipase 3D Structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>
{{#tree:id=OrganizedByTopic|openlevels=0|
 
*Eukaryote lipase:
 
**[[1hpl]] – hLip – horse <br />
**[[1hlg]] – hLip – human - gastric<br />
**[[3jw8]], [[3hju]] – mono-glyceride hLip<br />
**[[1jmy]] – hBSSL  <br />
**[[1akn]] – cBSSL – cattle <br />
**[[2bce]] - cBSSL (mutant) <br />
**[[1f6w]] - cBSSL – catalytic domain<br />
**[[3o0d]] – Lip – ''Yarrowia lipolytica''<br />
**[[4jei]] – YlLip (mutant)<br />
**[[1gpl]] – Lip – Guinea pig<br />
**[[3zpx]] – Lip – ''Ustilago maydis''<br />
 
*Prokaryote lipase:
 
**[[3guu]], [[1lbs]], [[1lbt]], [[1tca]], [[1tcb]], [[1tcc]] – CaLipA – ''Candida antarctica''<br />
**[[2veo]] – CaLipA – closed state<br />
**[[4k6g]] – CaLipB<br />
**[[3icv]], [[4k5q]], [[4k6h]], [[4k6k]] – CaLipB (mutant) <br />
**[[1gz7]], [[1lpm]], [[1lps]]– CrLip 2 – ''Candida  rugosa'' - closed state<br />
**[[1crl]], [[1trh]] – CrLip – open state<br />
**[[1llf]] – Lip – ''Candida cylindracea''<br />
**[[3g7n]] – Lip - ''Penicillium expansum''<br />
**[[1tia]] - Lip – ''Penicillium camemberti''<br />
**[[2qua]], [[2qub]] – LipA – ''Serratia marcescens''<br />
**[[2hih]] – Lip – ''Staphylococcus hyicus''<br />
**[[2fx5]] – Lip – ''Pseudomonas mendocina''<br />
**[[1yzf]] – Lip – ''Enterococcus faecalis''<br />
**[[1dt3]], [[1dt5]], [[1dte]], [[1du4]], [[1ein]], [[1tib]], [[4dyh]], [[4ea6]], [[4flf]], [[4gbg]], [[4gwl]] - TlLip - ''Thermomyces lanuginose''<br />
**[[1jfr]] – Lip – ''Streptomyces exfoliates''<br />
**[[1oil]] – BcLip - ''Burkholderia cepacia''<br />
**[[2lip]] – BcLip – open state<br />
**[[1cvl]] – Lip – ''Chromobacterium viscosum''<br />
**[[1lgy]] – Lip II – ''Rhizopus niveus''<br />
**[[1tic]] - Lip  – ''Rhizopus oryzae''<br />
**[[1thg]] – Lip – ''Geotrichum candidum''<br />
**[[3tgl]], [[4tgl]], [[1tgl]] – RmLip– ''Rhyzomucor miehei''<br />
**[[2zvd]] – PsLip - ''Pseudomonas sp.'' – open state<br />
**[[2z8x]] - PsLip – extracellular<br />
**[[2zj6]], [[2zj7]] – PsLip (mutant) <br />
**[[2z8z]] – PsLip(mutant) – closed state<br />
**[[3lip]], [[3a6z]] - Lip - ''Pseudomonas cepacia'' – open state<br />
**[[1qge]], [[1tah]] – Lip – ''Pseudomonas glumae''<br />
**[[2w22]] – Lip – ''Geobacillus thermocatenulatus''<br />
**[[1ji3]], [[1ku0]], [[4fmp]] – Lip – ''Bacillus stearothermophilus''<br />
**[[1ah7]] - Lip – ''Bacillus cereus''<br />
**[[2qxt]], [[2qxu]], [[1isp]], [[1i6w]], [[4fdm]] - BsLip  – ''Bacillus subtilis''<br />
**[[3d2a]], [[3d2b]], [[3d2c]], [[1t2n]], [[1t4m]], [[3qmm]], [[3qzu]], [[4fkb]] - BsLip (mutant) <br />
**[[2ory]] – Lip – ''Photobacterium lypoliticum''<br />
**[[2z5g]], [[2dsn]] – GzLip T1 – ''Geobacillus zalihae''<br />
**[[3umj]] – GzLip (mutant)<br />
**[[3p94]] – Lip – ''Parabacteroides distasonis''<br />
**[[3ngm]] – Lip – ''Gibberella zeae''<br />
**[[3auk]] - Lip – ''Geobacillus''<br />
**[[3uue]], [[3uuf]] – Lip – ''Malassezia globosa''<br />
**[[4hs9]] – Lip – ''Proteus mirabilis''<br />
 
*Lipase/colipase complexes.  The colipase is a co-enzyme whose binding to lipase optimizes the enzymatic activity
 
**[[1n8s]] – hLip+colipase II<br />
**[[1eth]], [[1lpa]] - Lip+colipase II - pig<br />
 
*Hormone-sensitive-lipases (LIPE) hydrolyze the first fatty acid of the triacylglycerol substrate
 
**[[3k6k]] – EstE7(LIPE) – metagenome library<br />
**[[3fak]], [[3dnm]] – EstE5(LIPE) – metagenome library<br />
**[[1evq]] – AaEst2(LIPE) – ''Alicyclobacillus acidocaldarius''<br />
**[[1u4n]] – AaEst2(LIPE) (mutant) <br />
 
*Putative lipases; Proteins with unknown function but structural similarity to lipase obtained in structural genomics projects.
 
**[[2rau]] - Lip – ''Sulfolobus solfataricus''<br />
**[[3bxp]], [[3d3n]] - Lip – ''Lactobacillus plantarum''<br />
**[[3e0x]] - Lip – ''Clostridium acetobutylicum''<br />
**[[1z8h]] – Lip – ''Nostoc sp.'' PCC 712<br />
**[[1vj3]] - Lip  – ''Nostoc sp.'' <br />
**[[3bzw]] – Lip - ''Bacteroides thetaiotaomicron''<br />
**[[2pbl]] – Lip - ''Silicibacter''
 
*Lipase + inhibitors
 
**[[3jwe]], [[3pe6]] - mono-glyceride hLip + SAR629 – covalent inhibitor<br />
**[[3l1h]] – EstE5(LIPE)+FeCl3  – noninvasive inhibitor<br />
**[[3l1i]], [[3l1j]] - EstE5(LIPE)+CuSO4 – noninvasive inhibitor<br />
**[[3lij]] - EstE5(LIPE)+ZnSO4– noninvasive inhibitor<br />
**[[3h18]], [[3h17]] - EstE5 (LIPE)+PMSF <br />
**[[3h19]], [[3h1b]], [[3h1a]] – EstE5 (LIPE)+methyl alcohol<br />
**[[3h1a]] – EstE5 SLIPE)+ethyl alcohol<br />
**[[3h19]] – EstE5 SLIPE)+isopropyl alcohol<br />
**[[3g9t]], [[3g9u]] - EstE5 (HSLIPE)+p-nitrophenyl butyrate<br />
**[[3g9z]] - EstE5 (LIPE) +p-nitrophenyl caprylate<br />
**[[2nw6]] – BcLip+ S inhibitor <br />
**[[4lip]], [[5lip]], [[1r4z]], [[1r50]] – BcLip+ Rc-(Rp,Sp)-1,2-dioctylcarbamoyl-glycero-3-O-phosphonate<br />
**[[1r4z]] – BsLip+Rc-IPG-phosphonate <br />
**[[1r50]] - BsLip+Sc-IPG-phosphonate <br />
**[[1k8q]] - Lip+phosphonate – dog <br />
**[[1ex9]] – Lip+Rc-(Rp,Sp)-1,2-dioctylcarbamoyl-glycero-3-O-phosphonate – ''Pseudomonas aeruginosa'' <br />
**[[5tgl]] – RmLip+N-hexyl-phosphonate <br />
**[[1lpb]] – Lip (pig)+colipase+C11 alkyl phosphonate <br />
**[[3icw]] – CaLipB (mutant) +methyl hydrogen R hexylphosphonate<br />
**[[3a70]] – PsLip+diethyl phosphate<br />
**[[4glb]] – TlLip + nitrobenzaldehyde<br />
**[[4kjx]] - TlLip + nitrobenzaldehyde + lauric acid<br />
**[[4n8s]] - TlLip + nitrobenzaldehyde + ethylacetoacetate<br />
 
*Lipase conjugated with analogs to its reaction intermediates
 
**[[1lpn]], [[1lpo]], [[1lpp]] – CrLip+ sulfonates <br />
**[[3rar]] – CrLip+ phosphonate <br />
**[[1qz3]] – EaEst2(mutant) (LIPE)+hexadecanesulfonate <br />
 
*Lipase showing bile-salt binding site
 
**[[1aql]] – cBSSL+taurocholate <br />
 
*Monoacylglycerol lipase
 
**[[3rm3]], [[4lhe]] - BaMAGL – ''Bacillus'' <BR />
**[[3hju]], [[3jw8]] - hMAGL  <BR />
**[[3rli]] – BaMAGL + PMSF<br />
**[[4ke7]], [[4ke8]], [[4ke9]] – BaMAGL + ligand<br />
**[[4ke6]], [[4kea]] – BaMAGL (mutant) + ligand<br />
**[[3jwe]], [[3pe6]] – hMAGL + inhibitor<br />
 
*Lipase with substrate bound at active site
 
**[[2zyh]] – AfLip (mutant)+fatty acid – ''Archaeoglobus fulgidus''<br />
**[[2zyi]], [[2zyr]], [[2zys]] - AfLip+fatty acid+ ion <br />
**[[1gt6]], [[4ghw]], [[4gi1]] – TlLip+ fatty acid - lipid ligand<br />
 
*Lipase conjugated to transition-state analogs showing the binding mode of the enzyme catalysis
 
**[[1ys1]] – BhLip+hexylphosphonic acid (R) 2-methyl-3-phenylpropyl ester <br />
**[[1ys2]] – BhLip+hexylphosphonic acid (S) 2-methyl-3-phenylpropyl ester<br /> 
**[[1hqd]] – Lip+1-phenoxy-2-acrtoxy butane – ''Pseudomonas cepacia'' <br />
 
*Lipase+lipase chaperone


**[[2es4]] – Lip+lipase chaperone C-terminal - ''Burkholderia glumae''
}}
==References==
==References==
<references />
<references />


[[Category:Topic Page]]
[[Category:Topic Page]]

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