Differences in the inhibition of coagulation factor XIII-A from animal species revealed by Michael Acceptor– and thioimidazol based blockers

Heil, Andreas; Weber, J; Büchold, Christian; Pasternack, Ralf; Hils, Martin

doi:10.1016/j.thromres.2013.02.008

Cited by 12 publications

(12 citation statements)

References 32 publications

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“…Lactoferrin has been shown to cleave and inactivate peptidases from bacterial pathogens [64]. Coagulation factor XIIIa and destabilase are multifunctional, but both can act as isopeptidases to break the isopeptide bonds in fibrin and the peptidoglycan of bacterial cell walls [65,66].…”

Section: Peptidase Families With An Origin In Animalsmentioning

confidence: 99%

Origins of peptidases

Rawlings

Bateman

2019

Biochimie

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a b s t r a c tThe distribution of all peptidase homologues across all phyla of organisms was analysed to determine within which kingdom each of the 271 families originated. No family was found to be ubiquitous and even peptidases thought to be essential for life, such as signal peptidase and methionyl aminopeptides are missing from some clades. There are 33 peptidase families common to archaea, bacteria and eukaryotes and are assumed to have originated in the last universal common ancestor (LUCA). These include peptidases with different catalytic types, exo-and endopeptidases, peptidases with different tertiary structures and peptidases from different families but with similar structures. This implies that the different catalytic types and structures pre-date LUCA. Other families have had their origins in the ancestors of viruses, archaea, bacteria, fungi, plants and animals, and a number of families have had their origins in the ancestors of particular phyla. The evolution of peptidases is compared to recent hypotheses about the evolution of organisms.

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Section: Peptidase Families With An Origin In Animalsmentioning

confidence: 99%

Origins of peptidases

Rawlings

Bateman

2019

Biochimie

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“…Factor XIII activity has been reported in a variety of intra‐ and extracellular physiological environments and has been implicated in numerous pathological events. Being the final player of the coagulation cascade, FXIIIA has been recognized as a promising target for novel anticoagulant agents, with a prospect of fewer side effects . When implementing new coagulation management regimes, it may be desirable, on the one hand, not to affect FXIII function in nonhemostatic events.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic and nonproteolytic activation mechanisms result in conformationally and functionally different forms of coagulation factor XIII A

et al. 2019

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Factor XIIIA (FXIIIA) is a transglutaminase that cross‐links intra‐ and extracellular protein substrates. FXIIIA is expressed as an inactive zymogen, and during blood coagulation, it is activated by removal of an activation peptide by the protease thrombin. No such proteolytic FXIIIA activation is known to occur in other tissues or the intracellular form of FXIIIA. For those locations, FXIIIA is assumed instead to undergo activation by Ca2+ ions. Previously, we demonstrated a monomeric state for active FXIIIA. Current analytical ultracentrifugation and kinetic experiments revealed that thrombin‐activated FXIIIA has a higher conformational flexibility and a stronger affinity toward glutamine substrate than does nonproteolytically activated FXIIIA. The proteolytic activation of FXIIIA was further investigated in a context of fibrin clotting. In a series of fibrin cross‐linking assays and scanning electron microscopy studies of plasma clots, the activation rates of FXIIIA V34X variants were correlated with the extent of fibrin cross‐linking and incorporation of nonfibrous protein into the clot. Overall, the results suggest conformational and functional differences between active FXIIIA forms, thus expanding the understanding of FXIIIA function. Those differences may serve as a basis for developing therapeutic strategies to target FXIIIA in different physiological environments. Enzymes Factor XIIIA ( EC 2.3.2.13)

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“…The functional expression of recombinant FXIII‐A 2 (A subunits) in insect cells, its respective purification and the synthesis of Michael acceptor (MA) transglutaminase blockers was recently described and will be briefly summarized below. Activation of blood coagulation factor XIII was achieved by high calcium ion concentrations instead of exposure to thrombin .…”

Section: Methodsmentioning

confidence: 99%

Structure‐Based Design of FXIIIa‐Blockers: Addressing a Transient Hydrophobic Pocket in the Active Site of FXIIIa

Stieler

Büchold²,

Schmitt³

et al. 2020

ChemMedChem

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Blood coagulation factor XIII (FXIII, F13) is considered to be a promising target for anticoagulants with reduced bleeding risk because of its unique position in the coagulation cascade downstream of thrombin. However, until now, no potent drug addressing FXIII has been available, indeed no compound has even entered clinical trials yet. In 2013, we published the co‐crystal structure of FXIII in the active state (FXIIIa°), thereby providing a detailed map of the active site for the rational design of potent FXIIIa blockers. Here we report, for the first time, a structure‐based approach to improving the affinity of FXIIIa inhibitors. FXIII was crystallized in complex with a methyl thiazole moiety to address a novel transient hydrophobic pocket close to the catalytic center. By subsequent structure‐based design to rationalize the introduction of an ethyl ester, the potency of the inhibitor was improved significantly compared to that of the parent lead compound. The occupancy of the hydrophobic pocket described here might turn out to be a key step in the development of a potent reversible and orally available FXIIIa blocker.

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Differences in the inhibition of coagulation factor XIII-A from animal species revealed by Michael Acceptor– and thioimidazol based blockers

Cited by 12 publications

References 32 publications

Origins of peptidases

Origins of peptidases

Proteolytic and nonproteolytic activation mechanisms result in conformationally and functionally different forms of coagulation factor XIII A

Structure‐Based Design of FXIIIa‐Blockers: Addressing a Transient Hydrophobic Pocket in the Active Site of FXIIIa

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