Proteases are essential participants in tissue remodeling, blood clotting, elimination of old or diseased cells, destruction of invading pathogens, and other physiologic functions. Left unchecked, however, proteolytic enzymes released into the blood by secretion or tissue damage can harm healthy tissue. Protection from indiscriminate proteolysis involves a battery of serum proteins that inhibit, and thereby limit the scope of, protease action.

Deficiency of α1-Antiproteinase Is Associated With Emphysema & Liver Disease

α1-Antiproteinase, a 394-residue glycoprotein is the principal serine protease inhibitor (serpin) in human plasma. Formerly called α1-antitrypsin, α1-antiproteinase inactivates trypsin, elastase, and other serine proteases by forming a covalent complex with them. α1-Antiproteinase, which constitutes >90% of the α1-albumin fraction in plasma, is synthesized by hepatocytes and macrophages. At least 75 polymorphic forms of this serpin, or Pi, exist. The major genotype is MM, whose phenotypic product is PiMM. A deficiency in α1-antiproteinase plays a role in some cases (~ 5%) of emphysema, particularly in subjects with the ZZ genotype (who synthesize PiZ) and in PiSZ heterozygotes, both of whom secrete lower levels of serpins than normal individuals.

Oxidation of Met₃₅₈ Inactivates α1-Antiproteinase

 In the lungs, oxidation of a key methionine residue, Met₃₅₈ , located in the protease-binding domain renders α1 antiproteinase unable to covalently bind and neutralize serine proteases. Individuals who use tobacco products or are regularly exposed to the smoke generated from burning fossil fuels are especially prone to oxidation of Met₃₅₈ . Unchecked by this key inhibitor, proteolytic activity in the lungs can contribute to the development of emphysema, particularly for patients possessing low levels of α1-antiproteinase (eg, PiZZ phenotype). Intravenous administration of serpins (augmentation therapy) has been used as an adjunct in the treatment of emphysema patients that exhibit α1-antiproteinase deficiency.

Individuals deficient in α1-antiproteinase are also at greater risk of lung damage from the accumulation of polymorphonuclear white blood cells in the lung that occurs during pneumonia and other respiratory infections. Deficiency of α1-antiproteinase is also implicated in α1 antitrypsin deficiency liver disease, a form of cirrhosis that afflicts persons possessing the ZZ phenotype. In these individuals, a mutation leading to the substitution of Glu342 by lysine produces a form of α1-antiproteinase that is prone to aggregation in the cisternae of the endoplasmic reticulum in hepatic cells.

α2-Macroglobulin Neutralizes Proteases & Targets Cytokines to Tissues

 α2-Macroglobulin, a member of the thioester plasma protein family, comprises 8 to 10% of the total plasma protein in humans. This homotetrameric glycoprotein, which is synthesized by monocytes, hepatocytes, and astrocytes, is the most abundant member of a group of homologous plasma proteins that include complement proteins C3 and C4. α2 Macroglobulin mediates the inhibition and clearance of a broad spectrum of truant proteases by a “Venus flytrap” mechanism that utilizes a 35-residue “bait domain” and an internal cyclic thioester linking a cysteine and a glutamine residue (Figure 1). Cleavage of the bait domain triggers a massive conformational change that results in the envelopment of the attacking protease. The reactive thioester then reacts with the protease to covalently link the two proteins. In addition, this conformational change exposes a sequence in α2 macroglobulin that is recognized by the cell surface receptors responsible for binding and clearing the α2-macroglobulin protease complex from the plasma.

Fig1. An internal cyclic thiol ester bond, as present in α2-macroglobulin. AAx and AAy are neighboring amino acids to cysteine and glutamine.

In addition to serving as the plasma’s predominant broad spectrum, or panproteinase, inhibitor, α2-macroglobulin also binds to and transports approximately 10% of the zinc carried by plasma (the remainder being transported by albumin) as well as cytokines such as platelet-derived growth factor and transforming growth factor β. α2-Macroglobulin routes these bound effectors toward particular tissues or cells. Once taken up, the complex dissociates, thereby freeing the cytokines to exert their modulatory effects on cell growth and function.

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العتبة العباسية المقدسة تطلق محاضرات محفل نهج البلاغة الأسبوعي في ذي قار

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الآخبار الصحية

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متى يصبح محيط الخصر "مؤشر خطر"؟

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رائحة كريهة في الجسم.. "علامة خفية" أخطر مما تتصور

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الآخبار التكنلوجية

مايكروسوفت تكشف عن الجيل الثاني من شرائحها للذكاء الاصطناعي

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مواضيع ذات صلة

Immunoglobulins Are Comprised of Multiple Polypeptide Chains

Intracellular Iron Homeostasis is Tightly Regulated

Clinical Biochemistry of Exercise: Biochemical Adaptation

Iron is Strictly Conserved

Haptoglobin Protects the Kidneys

The Levels of Certain Plasma Proteins Increase During Inflammation or Following Tissue Damage

Albumin is the Most Abundant Protein in Human Plasma

Biochemical Parameters for Assessing Athletic Performance

Clinical Biochemistry of Metabolic Substrates

Generalities on the Structure and Biochemistry of the Skeletal Muscle

Plasma Contains A Complex Mixture of Proteins

Intermediate Filaments Differ From Microfilaments & Microtubules