Cytochromeb₅ Reductase Reduces Methemoglobin

The ferrous, Fe²⁺, iron atoms in hemoglobin are susceptible to oxidation by reactive oxygen species (ROS). Hemoglobin in which one or more heme irons has been oxidized to the ferric (Fe³⁺) state is called methemoglobin. Ferric hemes do not bind oxygen, which not only reduces the number of O₂-binding sites, but can interfere with the cooperative interactions between the subunits of the hemoglobin tetramer. The ability to rescue methemoglobin by reducing ferric iron is thus of great physiologic importance. In red blood cells, methemoglobin reduction is catalyzed by the NADH–cytochromeb5 methemoglobin reductase system. The first component of the system, a flavoprotein named cytochrome b₅ reductase (also known as methemoglobin reductase), transfers electrons from NADH to the second component, Cytochromeb₅ :

Cyt b_5ox + NADH →Cytb_5red + NAD⁺

Reduced cytochrome b₅ then transfers the electrons to methemoglobin, reducing Fe³⁺ back to the Fe²⁺ state, which restores hemoglobin to its fully functional state:

Hb − Fe³⁺ + Cyt b_5red → Hb − Fe²⁺ + Cyt b_5ox

The ultimate source of the electrons used to reduce met hemoglobin is glycolysis, where NAD⁺ is reduced to NADH by the action of glyceraldehyde-3-phosphate dehydrogenase. The efficiency of this system is such that only trace quantities of methemoglobin are normally present in erythrocytes.

Methemoglobinemia Is Inherited or Acquired

Methemoglobinemia, the abnormal accumulation of methemoglobin, can arise from genetic abnormalities (inherited met hemoglobinemia) or from the ingestion of certain substances (acquired methemoglobinemia) such as nitrates, aniline, or sulfonamide antibiotics (Table 1). Affected patients often exhibit bluish discoloration of the skin and mucous mem branes (cyanosis). The inherited form most commonly arises from a deficiency in the quantity or activity of cytochrome b5 reductase, although mutations that affect the properties of cytochrome b5 itself have also been encountered. In rare instances, methemoglobinemia can result from mutations in hemoglobin itself, such as those affecting the proximal and distal histidine residues, that render it more susceptible to oxidation. Collectively referred to as hemoglobin M (HbM), these include HbM_Iwate , in which His87 in the α subunit is replaced by Tyr; HbM_Hyde Park , in which His92 of the β subunit is replaced by Tyr; HbM_Boston , in which His58 in the α subunits of hemoglobin is replaced by Tyr; and HbM_Saskatoon , in which His63 in the β subunit is replaced by Tyr. One exception to this pattern is HbMMilwaukee-1 , in which Val67 of the β subunit is replaced by Glu. All known carriers of HbM are heterozygotes.

Table1. Summary of the Causes of Some Important Disorders Affecting Red Blood Cells

Superoxide Dismutase, Catalase, & Glutathione Protect Blood Cells From Oxidative Damage

The radical anion superoxide, O2 ^{− •}, is generated in red blood cells by the autoxidation of hemoglobin to methemoglobin.

This potent ROS can react with and damage proteins, lipids, nucleotides, and other biomolecules. Approximately 3% of the hemoglobin of human blood undergoes auto-oxidation each day. In addition, oxidation of the iron storage protein ferritin by superoxide can result in the release of free Fe2+ and the subsequent iron-catalyzed generation of OH^•. Superoxide may thus produce the tis sue damage that occurs in persons suffering from abnormally high levels of iron in the body, known as iron overload. Iron overload is characteristic of individuals suffering from hereditary hemochromatosis, a genetic condition that causes the body to absorb excessive quantities of dietary iron. Another endogenous source of superoxide is the enzyme NADPH hemoprotein reductase (a cytochrome P450 reductase), which also catalyzes the reduction of the Fe3+ in methemoglobin to Fe2+.

Deficiency of Glucose-6-Phosphate Dehydrogenase Is an Important Cause of Hemolytic Anemia

The limited suite of metabolic pathways present in red blood cells renders them completely reliant on thepentose phosphate pathway or, to be more specific, the X-linked enzyme glucose-6-phosphate dehydrogenase, for the reduction of NADP+ to NADPH. Glucose-6-phosphate dehydrogenase deficiency is the most common of all enzymopathies (diseases caused by abnormalities of enzymes). More than 400 million people are estimated to carry one of the over 140 genetic variants of glucose-6-phosphate dehydrogenase. This deficiency is most common among natives of tropical Africa (and their African-American descendants), the Mediterranean, and certain parts of Asia.

Individuals harboring this deficiency are vulnerable to hemolytic anemia, a consequence of their inability to generate sufficient NADPH to maintain glutathione, a key intracellular antioxidant, in the reduced state (Figure 1). A deficiency in glucose-6-phosphate dehydrogenase renders red blood cells hypersensitive to oxidative stress and the formation of Heinz bodies, insoluble aggregates consisting of hemoglobin molecules whose —SH groups have become oxidized. Like sickle cell trait, the persistence of these genetic variants has been attributed to their potential to confer enhanced resistance to malaria.

Fig1. Summary of probable events causing hemolytic anemia due to deficiency of the activity of glucose 6-phosphate dehydrogenase (OMIM 305900).

Hemolytic Anemias Can Be Caused by Extrinsic, Intrinsic, or Membrane Specific Factors

Hemolytic anemia can be triggered by factors other than a deficiency in glucose-6-phosphate dehydrogenase (Figure 2). Extrinsic causes (beyond the erythrocyte membrane) include hypersplenism, in which the enlargement of the spleen causes red blood cells to become sequestered within this organ.

Fig2. Schematic diagram of some causes of hemolytic anemias. Extrinsic causes include hypersplenism, various antibodies, certain bacterial hemolysins, and some snake venoms. Causes intrinsic to the red cells include mutations that affect the structures of membrane proteins (eg, in hereditary spherocytosis and hereditary elliptocytosis), paroxysmal nocturnal hemoglobinuria (PNH), enzymopathies, abnormal hemoglobins, and certain parasites (eg, plasmodia causing malaria).

Erythrocytes also can lyse if attacked by incompatible anti bodies present in intravenously administered plasma or blood (eg, transfusion reaction). Immunologic incompatibilities may arise when an Rh+ fetus is carried by an Rh− mother (Rh disease) or as a consequence of an autoimmune disorder (eg, warm or cold antibody hemolytic anemias). Some infectious and toxic agents, such as the proteases and phospholipases found in many insect and reptile venoms, act by directly undermining the structural integrity of the erythrocyte membrane. Similarly, some infectious bacteria, including certain strains of Escherichia coli and clostridia, secrete factors that attack and lyse red blood cell membranes. These factors, collectively referred to as hemolysins, can be composed of proteins, lipids, or a combination thereof. Parasitic infections (eg, the plasmodia causing malaria) are also a major cause of hemolytic anemias in certain geographic areas.

The root cause of many hemolytic anemias is intracellular, also referred to as intrinsic. Gluocse-6-phosphate dehydrogenase deficiency falls into this category. Defects in the composition or structure of hemoglobin, called hemoglobinopathies, constitute the second major intrinsic cause of hemolysis. Most hemoglobinopathies, such as sickle cell anemia and the various thalassemias, are genetic in nature. In rare cases, hemolytic anemia can arise from an insufficiency in the enzyme pyruvate kinase. The resulting impairment of glycolysis reduces the production of the ATP required to power the export of excess water and Na+. The resulting osmotic pressure can compromise and potentially overwhelm the integrity of the erythrocyte membrane.

Mutations that affect the cytoskeletal proteins responsible for maintaining the erythrocyte’s biconcave shape and resistance to osmotic pressure are classified as membrane-specific causes of hemolytic anemia. The most important of these are hereditary spherocytosis and hereditary elliptocytosis, which arise from abnormalities in the amount or structure of the cytoskeletal protein spectrin. Defects may also occur in the synthesis of the glycophosphatidylinositol groups that anchor certain proteins, such as acetylcholinesterase and decay-accelerating factor, to the surface of the erythrocyte membrane, as is the case in paroxysmal nocturnal hemoglobinuria.

اخر الاخبار

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مشروب أحمر يخفض ضغط الدم "بشكل ملحوظ"

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مواضيع ذات صلة

Hypervariable Regions Confer Binding Specificity

Immunoglobulins Are Comprised of Multiple Polypeptide Chains

Serum Inhibitors Prevent Indiscriminate Proteolysis

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