Studies on the kinetics of plasminogen activation by tissue plasminogen activator

Rånby, Mats

doi:10.1016/0167-4838(82)90068-1

Cited by 357 publications

(199 citation statements)

References 12 publications

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“…Conformational changes of Glu-plasminogen mediated by binding of ligands to the AH-site, as defined m [1], are generally considered important for its rate of converston into plasmin [4][5][6][7][8][9][10]. Several laboratories have studted the overall kmet~c and bmding properties of the Glu-plasminogen activation systems, but the rate of the conformauonal change has httherto not been determined.…”

Section: Discussionmentioning

confidence: 99%

“…The overall dlssociat~on constant of this 6.aminohexanolc acld.Glu-plasminogen complex is K~ = 2.0 mM m good agreement with previous AH-slte results [l, 13, 14] The conformattonal change determines the overall rate of the hgand binding process, Its rate constant, 70 s "l (pH 7.8, 25°C), ~s approx=mately 20 t~mes largor tuan the values of the catalytic constant of plasmlnogen activator catalyzed conversion of Glu.plasmmogenhgand complexes into plasmm. Although such values differ somewhat, the reported k~s arc of the order of magmtude 0.5-5 s -t [6][7][8][9][10]. Llgands that induce conformattonal changes m Glu-plasmmogen facdltate ~ts activation.…”

Section: Discussionmentioning

confidence: 99%

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Stopped‐flow fluorescence kinetic studies of Glu‐plasminogen Conformational changes triggered by AH‐site ligand binding

Christensen

Mølgaard

1991

FEBS Letters

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Bmdtnil of 6-ammohexaaolu acid tO the AH.I)Ie, a weak lyline bittdln8 lib: tn Glu,plasmlnoilen, =liters the conformation of tile moleculc~ The kmel. ice= of the blndlnii and the ac=:ompanylnil ¢onformational chanlle are investljated at pH 7 I!, 2.~'C Chanlle~ of lama,tie protein iluor~ccnee ~ete measured as a function of time after raped mixing in a stopped.flew app*ratus, The results reflect a two.step ra~¢tto,t meehan,sm. Rapid ass~iation of Glu.plasmtnogen and 6-ammohe~anoi¢ nod (K) =,44 raM) followed by the conform.tional change (k= =69 (-= and k ,~ ,,. 3 s =1 with an overall dissc

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Stopped‐flow fluorescence kinetic studies of Glu‐plasminogen Conformational changes triggered by AH‐site ligand binding

Christensen

Mølgaard

1991

FEBS Letters

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“…The binding of plasminogen to C-terminal Lys residues on cell surface proteins and fibrin clots increases its activation up to 1000-fold [75][76][77][78]. It was shown that plasma CPU and CPN cleave C-terminal Lys residues on these plasminogen "receptors" and thereby downregulate plasminogen activation [77,78].…”

Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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Human carboxypeptidase N (CPN) was discovered in the early 1960s as a plasma enzyme that inactivates bradykinin and was identified 8 years later as the major "anaphylatoxin inactivator" of blood. CPN plays in important role in protecting the body from excessive buildup of potentially deleterious peptides that normally act as local autocrine or paracrine hormones. This review summarizes the structure, enzymatic properties and function of this important human enzyme, including insights gained by the recent elucidation of the crystal structure of the CPN catalytic subunit and structural modeling of the non-catalytic regulatory 83 kDa subunit. We also discuss its physiological role in cleaving substrates such as kinins, anaphylatoxins, creatine kinase, plasminogen receptors, hemoglobin and stromal cell-derived factor-1α (SDF-1α). HistoryCarboxypeptidases were initially isolated from pancreatic extracts and so were associated with protein and peptide degradation in the digestive tract [1][2][3][4]. However, work beginning in the early 1960's by Erdös and Sloane [5] revealed the presence of a novel carboxypeptidase in the blood that plays a regulatory role by inactivating bradykinin via removal of its C-terminal Arg residue. (Subsequent research some 2 decades later led to the discovery of a second kinin B 1 receptor activated by the carboxypeptidase metabolite that is its endogenous agonist -see below). Initially it was assumed that the enzyme represents a circulating form of pancreatic carboxypeptidase B, but this was disproved by the characterization of its enzymatic properties [5][6][7][8], which was later borne out by biochemical studies, sequence analysis [9][10][11][12][13][14][15] and ultimately X-ray crystallography [16]. To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19]. It has since been re-discovered many times as other substrates were found and so has acquired aliases such as creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, lysine carboxypeptidase and protaminase [8,17,20,21]. The most notable was the finding by Bokisch and Müller-Eberhard in 1969 -70 [22,23] that the human plasma "anaphylatoxin inactivator" is identical with CPN. This finding explains our interest in the work of Dr. Tony Hugli, who has made many seminal contributions to the understanding of the structure and function of anaphylatoxins [24][25][26][27]. In Send Correspondence and Proofs To: Randal A. Skidgel, PhD, Dept. of Pharmacology (M/C 868), Univ. of Illinois College of Medicine, 835 S. Wolcott, Chicago, IL 60612, Phone: 312-996-9179, FAX: 312-996-1648, EMAIL: E-mail: rskidgel@uic.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript w...

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“…Native tissue PA (Mr -70 000) is a one-chain polypeptide and has been shown by amino acid and cDNA sequence analysis to be homologous to serine protease zymogens [3,4]. However, native one-chain tissue PA is an active serine protease [5][6][7]. This irregularity is reflected in (or perhaps due to) a lysine residue at a position in the activation cleavage site region (-Arg&Ile-Lys-Gly-Gly-) that typically harbours a hydrophobic residue [8].…”

Section: Introductionmentioning

confidence: 99%

“…The B chain originates from the Cterminal of one-chain tissue PA and is homologous to trypsin [3]. In the presence of fibrin one-chain and two-chain tissue PA have similar enzymatic properties [6,7], but in the absence of fibrin the two-chain form is generally 2-10-fold more efficient [5,7,9,10].…”

Section: Introductionmentioning

confidence: 99%

Isolation of two variants of native one‐chain tissue plasminogen activator

et al. 1982

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The native one-chain tissue plasminogen activator from the human melanoma cell line (Bowes) occurs in two variants as demonstrated by sodium dodecylsulphate-polyacrylamide gel electrophoresis of reduced and carboxymethylated samples. The two variants were isolated by affinity chromatography on arginineSepharose using a guanidinium-HC1 gradient, in the order of elution, the variants were designated tissue plasminogen activator I and II. Variant I was found to be 3000 Mr larger than variant II and the difference was found to reside in the N-terminal half of the molecule. No substantial difference in carbohydrate content nor in enzymatic activity was demonstrated. Plasminogen activator Tissue plasminogen activator Extrinsic plasminogen activator A rginine-Sepharose chromatographyCarbohydrate Enzymatic activity

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Studies on the kinetics of plasminogen activation by tissue plasminogen activator

Cited by 357 publications

References 12 publications

Stopped‐flow fluorescence kinetic studies of Glu‐plasminogen Conformational changes triggered by AH‐site ligand binding

Stopped‐flow fluorescence kinetic studies of Glu‐plasminogen Conformational changes triggered by AH‐site ligand binding

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Isolation of two variants of native one‐chain tissue plasminogen activator

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