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Human Plasma Lecithin:Cholesterol Acyltransferase (LCAT) On the role of essential carboxyl groups in catalysis

  • Matti Jauhiainen
  • Peter J. Dolphin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 285)

Abstract

LCAT is one of the three major enzymes of plasma lipoprotein metabolism and catalyses the transacylation of the fatty acid at the sn-2 position of lecithin to the 3-hydroxyl group of cholesterol forming lysolecithin and cholesteryl ester within the plasma compartment. In a series of reports (1–4) we elucidated the chemical catalytic mechanism of this important enzyme which now appears to bear some similarities to that of the recently discovered lecithin:retinol acyltransferase (LRAT) (5). Incorporating the previous observation that LCAT can esterify lysolecithin present in LDL (6) and the recent observations of Sorci Thomas et al. (7) the major features of the LCAT catalytic mechanism can be summarized as shown in Figure 1. The sn-2 carbonyl carbon of lecithin, present in plasma HDL, is initially subjected to nucleophilic attack by the oxygen atom of Serine-181 with the resultant formation of a transient tetrahedral adduct which decays with bond cleavage to yield a fatty acylated serine residue. The fatty acid is then internally transacylated to one of two vicinal cysteine residues (Cys-31 and Cys-184) by a mechanism that appears irreversible. Either cysteine residue can then donate its fatty acid moiety to cholesterol forming cholesteryl ester. The lysolecithin acyltransferase or LAT reaction is proposed to involve only Ser-181 which becomes acylated upon lecithin cleavage and donates its fatty acid back to another lysolecithin molecule when the concentration of the lysolipid is sufficiently high. Cholesteryl ester can be both formed and cleaved by LCAT (7). During cleavage the fatty acid is retained by the enzyme and transferred to another cholesterol molecule. Fatty acid originating as cholesteryl ester does not appear to be transferred to lysolecithin (7) and we thus propose that either of the vicinal cysteine residues mediates the cleavage of cholesteryl ester with the formation of a fatty acylated residue.

Keywords

Cholesteryl Ester Catalytic Triad Phenylboronic Acid Cholesterol Acyltransferase Fatty Acid Moiety 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1).
    JauhiainenJVL, and Dolphin,PJ. (1986) J. Biol. Chem. 261, 7032–7043.PubMedGoogle Scholar
  2. 2).
    Jauhiainen,M., Ridgway,N.D., and Dolphin,P.J. (1987) Biochim. Biophys. Acta. 918, 175–188.PubMedGoogle Scholar
  3. 3).
    Jauhiainen,M., Stevenson,KJ., and Dolphin, P.J. (1988) J. Biol. Chem. 263, 6525–6533.PubMedGoogle Scholar
  4. 4).
    Jauhiainen,M., Yuan,W., Gelb,M.H., and Dolphin,P.J. (1989) J. Biol. Chem. 264, 1963–1967.PubMedGoogle Scholar
  5. 5).
    MacDonald,P.N., and Ong,D.E. (1988) J. Biol. Chem. 263, 12478–12482.PubMedGoogle Scholar
  6. 6).
    Subbaiah,P.V., Albers,J.J., Chen,C-H., and Bagdade,J.D. (1980) J. Biol. Chem. 255, 9275–9280.PubMedGoogle Scholar
  7. 7).
    Sorci-Thomas,M., Babiak,J., and Rudel,L.L. (1990) J. Biol. Chem. 265, 2665–2670.PubMedGoogle Scholar
  8. 8).
    Kraut, J. (1977) Ann. Rev. Biochem. 46, 331–358.PubMedCrossRefGoogle Scholar
  9. 9).
    Brady,L., Brzozowski, A.M., Derewenda,Z.S., Dodson,E., Dodson,G., Tolley,S., Turkenberg, J.P., Christiansen,L., Hugh-Jensen,B., Norskov,L., Thim,L., and Menge,U. (1990) Nature 343, 767–770.PubMedCrossRefGoogle Scholar
  10. 10).
    Winkler,F.K., D’Arcy,A., and Hunziker,W. (1990) Nature 343, 771–774.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Matti Jauhiainen
    • 1
  • Peter J. Dolphin
    • 2
  1. 1.Department of BiochemistryNational Public Health InstituteHelsinkiFinland
  2. 2.Department of BiochemistryDalhousie UniversityHalifaxCanada

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