Carboxypeptidase A-catalyzed direct conversion of leukotriene C4 to leukotriene F4.
Leukotrienes (LTs) are 5-lipoxygenase (5-LO)-derived arachidonic metabolites that constitute a potent set of lipid mediators produced by inflammatory cells. Leukotriene A(4), a labile allylic epoxide formed from arachidonic acid by dual 5-LO activity, is the precursor for LTB(4) and LTC(4) synthesis. LTC(4) is further transformed enzymatically by the sequential action of gamma-glutamyltranspeptidase and dipeptidase to LTD(4) and LTE(4), respectively. In this report, we present evidence that bovine pancreatic carboxypeptidase A (CPA), which shares significant sequence homology with CPA in mast cell granules, catalyzes the conversion of LTC(4) to LTF(4) via the hydrolysis of an amide bond. The identity of CPA-catalyzed LTC(4) hydrolysis product as LTF(4) was confirmed by several analytical criteria, including enzymatic conversion to conjugated tetraene by soybean LO, conversion to LTE(4) by gamma-glutamyltranspeptidase, cochromatography with the standard LTF(4) and positive-ion fast-atom bombardment mass spectral analysis. Thus, it appears that the physiological significance of this single-step transformation may point toward a major cellular homeostatic mechanism of metabolizing LTC(4), a potent bronco- and vasoconstrictor, to a less potent form of cysteinyl LTs.
Reddanna
Pallu
P
College of Life Sciences, University of Hyderabad, Hyderabad 500134, India.
Prabhu
K Sandeep
KS
Whelan
Jay
J
Reddy
C Channa
CC
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002268:Carboxypeptidases / Q000494:pharmacology*; D043422:Carboxypeptidases A; D002412:Cations; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D006868:Hydrolysis; D017997:Leukotriene C4 / Q000378:metabolism*; D013058:Mass Spectrometry; D008956:Models, Chemical; D013189:SRS-A / Q000031:analogs & derivatives* / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D015032:Zinc / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000596:Amino Acids; D002412:Cations; D013189:SRS-A; D017997:Leukotriene C4; C037113:leukotriene F-4; D001094:Arachidonate 5-Lipoxygenase; D005723:gamma-Glutamyltransferase; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D015032:Zinc