A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion.
Human alpha2-antiplasmin (alpha2AP), also known as alpha2-plasmin inhibitor, is the major inhibitor of the proteolytic enzyme plasmin that digests fibrin. There are 2 N-terminal forms of alpha2AP that circulate in human plasma: a 464-residue protein with Met as the N-terminus, Met-alpha2AP, and a 452-residue version with Asn as the N-terminus, Asn-alpha2AP. We have discovered and purified a proteinase from human plasma that cleaves the Pro12-Asn13 bond of Met-alpha2AP to yield Asn-alpha2AP and have named it antiplasmin-cleaving enzyme (APCE). APCE is similar in primary structure and catalytic properties to membrane-bound fibroblast activation protein/seprase for which a physiologic substrate has not been clearly defined. We found that Asn-alpha2AP becomes cross-linked to fibrin by activated factor XIII approximately 13 times faster than native Met-alpha2AP during clot formation and that clot lysis rates are slowed in direct proportion to the ratio of Asn-alpha2AP to Met-alpha2AP in human plasma. We conclude that APCE cleaves Met-alpha2AP to the derivative Asn-alpha2AP, which is more efficiently incorporated into fibrin and consequently makes it strikingly resistant to plasmin digestion. APCE may represent a new target for pharmacologic inhibition, since less generation and incorporation of Asn-alpha2AP could result in a more rapid removal of fibrin by plasmin during atherogenesis, thrombosis, and inflammatory states.
Lee
Kyung N
KN
Department of Medicine, University of Oklahoma Sciences Center, Oklahoma City, OK 73190, USA. kyunglee@ouhsc.edu
Jackson
Kenneth W
KW
Christiansen
Victoria J
VJ
Chung
Keun H
KH
McKee
Patrick A
PA
D000595:Amino Acid Sequence; D026122:Factor XIIIa / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D005342:Fibrinolysis; D006801:Humans; D007700:Kinetics; D012697:Serine Endopeptidases / Q000097:blood* / Q000302:isolation & purification* / Q000502:physiology; D000979:alpha-2-Antiplasmin / Q000378:metabolism / Q000502:physiology*
D000979:alpha-2-Antiplasmin; D005337:Fibrin; D026122:Factor XIIIa; D012697:Serine Endopeptidases; C487177:antiplasmin-cleaving enzyme, human; D005341:Fibrinolysin