肝素钠分子结构

/wiki/HeparinDESCRIPTIONHeparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2)2-deoxy-2-sulfamino-α-D-glucose 6-sulfate, (3) ß-D-glucuronic acid, (4)2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2) > (1) > (4) > (3) > (5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.Structure of Heparin Sodium (representative subunits):HeparinsHeparin - StructureHeparin is a mucopolysaccharide with a molecularweight ranging from 6,000 to 40,000 Da. The average molecular of most commercial heparin preparations is in the range of 12,000 - 15,000. The polymeric chain is composed of repeating disaccharide unit of D-glucosamine and uronic acid linked by 1¯¯>4 interglycosidic bond. The uronic acid residue could be either D-glucuronic acid or L-iduronic acid. (Structure below) Few hydroxyl groups on each of these monosaccharide residues may be sulfated giving rise to a polymer with that is highly negatively charged. The average negative charge of individual saccharide residues is about 2.3.Structure - Activity RelationshipThe key structural unit of heparin is a uniquepentasaccharide sequence (below). This sequence consists of three D-glucosamine and two uronic acid residues. The central D-glucosamine residue contains a unique 3-O-sulfate moiety that is rare outside of this sequence. Four sulfate groups on the D-glucosamines, encircled in the figure below, are found to be critical for retaining high anticoagulant activity. Elimination of any one of them results in a dramatic reduction in the anticoagulant activity. Removal of the unique3-O-sulate group results in complete loss of the anticoagulant activity. Removal of sulfate groups other than the critical ones seems to not affect the anticoagulant activity.MetabolismBecause of its highly acidic sulfate groups, heparinexits as the anion at physiologic pH and is usually administered as the sodium salt.Heparin is partially metabolized in the liver by heparinase to uroheparin, which has only slight antithrombin activity. Twenty to fifty percent is excreted unchanged. The heparin polysaccharide chain is degraded in the gastric acid and must therefore be administered intravenously or subcutaneously. Heparin should not be given intramuscularly because of the danger of hematoma formation.PharmacologyHeparin is relatively non-toxic. However, parenteral administration precludes its long-term use. It is generally given to postoperative patients and to those with acute infarctions requiring immediate anticoagulant action.Heparin overdose or hypersensitivity may result inexcessive bleeding. Protamines, highly positively charged low-molecular-weight proteins, are used as anti-dote for excessive bleeding complications.Biochemical MechanismHeparin, containing the unique five-residuesequence (shown above), forms a high-affinity complex with antithrombin. The formation of antithrombin - heparin complex greatly increases the rate of inhibition of two principle procoagulant proteases, factor Xa and thrombin. The normally slow rate of inhibition of both these enzymes (~ 103- 104M-1s-1) by antithrombin alone (see graph below) is increased about a 1,000-fold by heparin. Accelerated inactivation of both the active forms of proteases prevents the subsequent conversion of fibrinogen to fibrin that is crucial for clot formation.Low-Molecular-Weight (LMW) HeparinAs the name implies low-molecular-weight heparinsare preparations that have lower average molecular weight than heparin. The average molecular weight of these LMW heparins typically ranges from 2,000 to 8,000 Da. They are made by enzymatic or chemical controlled hydrolysis of unfractionated heparin. These molecules have very similar chemical structure as unfractionated heparin except for some changes that may have been introduced due to the enzymatic or chemicaltreatment. The mechanism of action of these drugs is the same as full-length heparin.The overall advantage in the use of these LMWheparins appears to be in the decreased need for monitoring patients in comparison to heparin. Differences of opinion exist and further testing will determine whether these will continue to be used. The first LMW heparin, enoxaparin, has been approved for preventing blood clots following hip replacement surgery.A polymer classified as a mucopolysaccharide or a glycosoaminoglycan. It is biosynthesized and stored in mast cells of various mammalian tissues, particularly liver, lung and mucosa. It is typically employed as an anticoagulant. It binds to antithrombin III, a naturally occurring plasma protease inhibitor, accelerating the rate at which antithrombin III inhibits coagulation proteases (factor Xa and thrombin). The activity of heparin as an anticoagulant has been shown to relate to the molecular weight. In the range of 6-12 kDa, heparin apparently binds to AT-III in a 1:1 stoichiometry; however, heparin with a molecular weight of 20 kDa can have two binding regions for AT-III. The probability of a third region is negligible. There is a correlation between molecular weight and anticoagulant activity, but it is linear only over a narrow range (8-12 kDa). Low molecular weight heparins (below approximately 8000; produced by oxidative depolymerization) inhibit AT-III but have a higher ratio of anti-factor Xa to anti-AT-III activity than regular heparin. They have lowered effect on platelet aggregation than normal heparin, and has no significant effect on blood coagulation tests. Dosages of these low molecular weight heparins cannot be equated to those of normal molecular weight heparins. Inhibits the IP3-activated Ca2+ release channel of the endoplasmic reticulum. Reported to activate the ryanodine receptor. Practically insoluble in alcohol, acetone, benzene.。