| 词条 | Lipstatin |
| 释义 |
| Watchedfields = changed | verifiedrevid = 443611742 | ImageFile = Lipstatin.svg | ImageSize = 250px | IUPACName = [(2S,4Z,7Z)-1-[(2S,3S)-3-Hexyl-4-oxooxetan-2-yl]trideca-4,7-dien-2-yl] (2S)-2-formamido-4-methylpentanoate | OtherNames = (2S,4Z,7Z)-1-[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]-4,7-tridecadien-2-yl N-formyl-L-leucinate |Section1={{Chembox Identifiers | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 7981411 | InChI = 1/C29H49NO5/c1-5-7-9-11-12-13-14-15-16-18-24(34-29(33)26(30-22-31)20-23(3)4)21-27-25(28(32)35-27)19-17-10-8-6-2/h12-13,15-16,22-27H,5-11,14,17-21H2,1-4H3,(H,30,31)/b13-12-,16-15-/t24-,25-,26-,27-/m0/s1 | InChIKey = OQMAKWGYQLJJIA-CUOOPAIEBU | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C29H49NO5/c1-5-7-9-11-12-13-14-15-16-18-24(34-29(33)26(30-22-31)20-23(3)4)21-27-25(28(32)35-27)19-17-10-8-6-2/h12-13,15-16,22-27H,5-11,14,17-21H2,1-4H3,(H,30,31)/b13-12-,16-15-/t24-,25-,26-,27-/m0/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = OQMAKWGYQLJJIA-CUOOPAIESA-N | CASNo_Ref = {{cascite|correct|??}} | CASNo = 96829-59-3 | MeSHName = Lipstatin | PubChem = 9805651 | SMILES = O=C(O[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)C\\C=C/C\\C=C/CCCCC)[C@@H](NC=O)CC(C)C }} |Section2={{Chembox Properties | C=29 | H = 49 | N=1 | O=5 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }}Lipstatin is a potent, irreversible inhibitor of pancreatic lipase. It is a natural product that was first isolated from the Actinobacterium Streptomyces toxytricini.[1] The popular antiobesity drug orlistat (trade names Xenical and alli) is a saturated derivative of lipstatin. BiosyntheisLipstatin is composed of a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-β-lactone 22 carbon backbone from fatty acid synthesis pathway and an N-formyl-L-leucine group ester linked to the 5-hydroxyl group of the back bone. The composts of the lipstatin are ultimately from linoleic acid, octanoic acid, and L-leucine.[2] The 22 carbon β-lactone moiety is derived from Claisen condensation between 3-hydroxytetradeca-5,8-dienyl-CoA derived from linoleic acid and hexyl-malonyl-ACP derived from octanoic acid.[2] [3][5]Linoleic acid is first attached to CoA through some acyl-CoA synthetase homologue synthesized by lipstatin biosynthetic operons (Lst) and goes through two β-oxidaition to hydroxytetradeca-5,8-dienyl-CoA. 3’ hydroxyl group from solution H2O is added by enoyl reductase homologue followed by enoyl hydratase homologue.[4] Octanoic acid is also attached to CoA through similar acyl-CoA synthetase homologue (LstC) to form octanoyl-CoA. Octanoyl-CoA is 2’ carboxylated and loaded to acyl carrier protein (ACP) borrowed from primary metabolism to form hexyl-malonyl-ACP.[5] The β-lactone ring formed by reduction of 3-keto group by 3-hydroxysteroid dehydrogenase homologue followed by a spontaneously nucleophilic attack of the 3-hydroxyl group on the carbonyl of the ACP-tether acyl intermediate. One articles pointed out this step is the last step after esterification of The N-formyl-L-leucine group.[2] The N-formyl-L-leucine group is derived from L-leucine. L-leucine was activated by LstE forming thioester and its α-amine group is formylated by LstF. Finally, 5-hydroxyl of 22 carbon β-lactone backbone nucleophilic attacks on the acyl carbon of the formyl-leucine and forms the lipstatin.[2] See also
References1. ^{{cite journal |vauthors=Weibel E, Hadvary P, Hochuli E, Kupfer E, Lengsfeld H |title=Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity |journal=J Antibiot (Tokyo) |volume=40 |issue=8 |pages=1081–5 |year=1987 |pmid=3680018 |doi=10.7164/antibiotics.40.1081}} 2. ^1 2 3 {{Cite journal|last=Bai|first=Tingli|last2=Zhang|first2=Daozhong|last3=Lin|first3=Shuangjun|last4=Long|first4=Qingshan|last5=Wang|first5=Yemin|last6=Ou|first6=Hongyu|last7=Kang|first7=Qianjin|last8=Deng|first8=Zixin|last9=Liu|first9=Wen|date=2014-12-15|title=Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase|url=http://aem.asm.org/content/80/24/7473|journal=Applied and Environmental Microbiology|language=en|volume=80|issue=24|pages=7473–7483|doi=10.1128/AEM.01765-14|issn=0099-2240|pmc=4249243|pmid=25239907}} 3. ^{{Cite journal|last=Goese|first=Markus|last2=Eisenreich|first2=Wolfgang|last3=Kupfer|first3=Ernst|last4=Stohler|first4=Peter|last5=Weber|first5=Wolfgang|last6=Leuenberger|first6=Hans G.|last7=Bacher|first7=Adelbert|date=2001-06-01|title=Biosynthesis of Lipstatin. Incorporation of Multiply Deuterium-Labeled (5Z,8Z)-Tetradeca-5,8-dienoic Acid and Octanoic Acid|journal=The Journal of Organic Chemistry|volume=66|issue=13|pages=4673–4678|doi=10.1021/jo010230b|issn=0022-3263}} 4. ^{{Cite journal|last=Goese|first=Markus|last2=Eisenreich|first2=Wolfgang|last3=Kupfer|first3=Ernst|last4=Weber|first4=Wolfgang|last5=Bacher|first5=Adelbert|date=2000-07-14|title=Biosynthetic Origin of Hydrogen Atoms in the Lipase Inhibitor Lipstatin|url=http://www.jbc.org/content/275/28/21192|journal=Journal of Biological Chemistry|language=en|volume=275|issue=28|pages=21192–21196|doi=10.1074/jbc.M003094200|issn=0021-9258|pmid=10801870}} 5. ^1 {{Cite journal|last=Demirev|first=Atanas V.|last2=Khanal|first2=Anamika|last3=Sedai|first3=Bhishma R.|last4=Lim|first4=Si Kyu|last5=Na|first5=Min Kyun|last6=Nam|first6=Doo Hyun|date=2010-05-02|title=The role of acyl-coenzyme A carboxylase complex in lipstatin biosynthesis of Streptomyces toxytricini|journal=Applied Microbiology and Biotechnology|language=en|volume=87|issue=3|pages=1129–1139|doi=10.1007/s00253-010-2587-2|issn=0175-7598|pmc=2886142|pmid=20437235}} 6 : Hydrolase inhibitors|Lactones|Oxetanes|Carboxylate esters|Formamides|Lipase inhibitors |
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