Academic literature on the topic 'Inhibiteur enzyme conversion'

Tracking down the metabolic basis of a remarkable human single-gene genetic disease provided the insight required to discover drugs to prevent prostate gland growth in aging men (benign prostatic hyperplasia, BPH) and prevent hair loss in men (male pattern baldness). Victims of this genetic disease are born with the appearance of females and are recognized as such. However, at puberty, they undergo a transformation and develop the characteristics of males. The underlying genetic defect is a mutation in the gene that codes for the enzyme 5-alpha reductase (5AR), which promotes conversion of testosterone (T) into the more potent male sex hormone dihydrotestosterone (DHT). Lack of sufficient DHT in utero prevents the full expression of male anatomy at birth, an issue that is corrected at the time of puberty when a surge of male sex hormones occurs. These men have a very small prostate gland that never grows, do not lose their hair, and do not get acne. This strongly suggests that DHT is the causative agent of BPH, male pattern baldness, and acne. An inhibitor of 5AR would create the functional equivalent of the genetic defect and would be expected to be effective in shrinking an enlarged prostate gland and slowing or preventing hair loss and acne in men. Finasteride is such an inhibitor and has met expectations. It is marketed as Proscar for BPH and Propecia for male pattern baldness. Finasteride is a teratogen (can cause birth defects) and has not been developed for acne for that reason.

The fibrinolytic system plays a vital role in maintaining vital organ homeostasis. Fibrinolysis, defined as the dissolution of fibrin (the major scaffold for intravascular thrombus), is the process that regulates thrombus growth after hemostasis has been achieved, thus preserving tissue perfusion. An understanding of fibrinolysis has led to the development of pharmacologic agents that can be used in the treatment of arterial and venous thrombotic disorders, including acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. Fibrinolytic therapy makes use of the vascular system’s intrinsic defense mechanism by accelerating and amplifying the conversion of an inactive enzyme precursor (zymogen), plasminogen, to the active enzyme plasmin. In turn, plasmin hydrolyzes several key bonds in the fibrin (clot) matrix, causing dissolution (lysis). A single-chain glycoprotein consisting of 790 amino acids, plasminogen is converted to plasmin by cleavage of the Arg560–Val561 peptide bond. The plasminogen molecule also contains specific lysine binding sites, which mediate its interaction with fibrin and α2-plasmin inhibitor. A serine protease with trypsinlike activity, plasmin attacks lysyl and arginyl bonds of fibrin at two principal sites: (1) the carboxyterminal portion α-chain (polar region) and (2) the coiled coil connectors containing α-, β-, and γ-chains. The ability of a fibrinolytic agent to dissolve an occlusive thrombus is determined by several factors. After administration the agent must be delivered to, perfuse, and ultimately infiltrate the thrombus while concomitantly being provided with an adequate amount of substrate (plasminogen) and the appropriate metabolic environment for an enzymatic reaction (conversion of plasminogen to plasmin) to take place. The intrinsic composition or ultrastructure of a thrombus also affects its lysability. Changes in the total amount and distribution of blood flow determine oxygen delivery to metabolically active tissues. They also determine the delivery of enzymatic substrate and plasminogen activators to the occlusive thrombus. In the heart, coronary blood flow correlates directly with mean arterial pressure. The flow-pressure curve is relatively flat above 65 to 70 mmHg, but becomes steeper as the mean arterial pressure decreases below this point. The relationship within the brain is more complex.

We developed amidolytic assays to determine human Factor Xlla, Factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic substrates pro-phe-arg-pNA (S2302 or chromozym PK), glu-pro-arg-pNA (S2366), ile-glu-(piperidyl)-gly-arg-pNA (S2337), and ile-glu-gly-arg-pNA (S2222) were tested for their suitability as substrates in these assays. 8-Factor Xlla, Factor XIa and plasma kallikrein each exhibit considerable activity towards a number of these substrates. This precludes direct quantitation of the individual enzymes when large a

The inhibition of the thrombin-mediated signal transfer by a common irreversible inhibitor Z of the factor Xa complex (Xc a) and thrombin has been analysed for the two-step process of the Xc a-triggered formation of thrombin andthe consecutive splitting ok a thrombin-specific substrate S. Assuming that both proteolytic processes follow simple Michaelis—Menten kinetics, that the inhibition reactions are second-order and that the prothrombin and irreversible inhibitor are in excess it can be shown that:1. clotting time (tc) is inversely proportional to the time-averaged thrombin concentration2.

We have previously demonstrated that 15-HETE, a mitogen for fetal bovine aortic endothelial cells (FBAECs), caused an accumulation of diglyceride (DG). Stimulation of DNA synthesis by 0AG (a synthetic DG analog) suggested that this mitogenic effect was mediated via elevation of cellular DG levels. In the present study we have delineated the mechanism by which 15-HETE causes DG accumulation by evaluating the effects of 15-HETE on the phosphati-dylinositol (PI) cycle. In [3H]inositol labeled cells, 15-HETE caused a decrease in PI content under both basal conditions (27%) and following A23187 sti

In physiologic and pathologic processes such as hemostasis, thrombosis and inflammation, multiple cell types are brought into close proximity - thereby increasing the possibility of metabolic interactions in the microenvironment. Activated platelets synthesize12-hydroxyeicosatetraenoic acid (12-HETE) in the presence or absence of aspirin. During a cell-cell interaction, platelet 12-HETE is metabolized by a cytochrome P-450 enzyme system in unstimulated neutrophils to 12.20-dihydroxyeicosatetraenoic acid (12,20-DiHETE). Recently, we observed time-dependent formation of a new eicosanoid followin

R59022 is a recently described inhibitor of the enzyme DG kinase [1], which converts DG to phosphatidic acid. While R59002 inhibits DG conversion in platelets resulting in enhanced protein kinase C (PrkC) activation [1], little is known on its effect on other platelet responses. In this study, we have examined the effect of R59022 on agonist-induced platelet aggregation and [14C]-5-hydroxytryptamine (5HT) release using washed human platelets. With a sub-maximal concentration of thrombin (T, 0.05U/ml) R59022 (10-30μM) significantly potentiated T-induced platelet aggregation and [14C]-5HT releas