Impairment of the Pentose Phosphate Pathway Leads to Erythrocyte Hemolysis

Genetic defects of glucose-6-phosphate dehydrogenase, with consequent impairment of the generation of NADPH, are common in populations of Mediterranean and Afro-Caribbean origin. The gene is on the X chromosome, so it is mainly males who are affected. Some 400 million people carry a mutated gene for glucose-6-phosphate dehydrogenase, making it the most common genetic defect, but most are asymptomatic. In some populations, glucose-6-phosphatase deficiency is common enough for it to be regarded as a genetic polymorphism. The distribution of mutant genes parallels that of malaria, suggesting that being heterozygous confers resistance against malaria. The defect is manifested as red cell hemolysis(hemolytic anemia)when susceptible individuals are subjected to oxidative stress (see Chapter 45) from infection, drugs such as the antimalarial primaquine, and sulfonamides, or when they have eaten fava beans (Vicia faba—hence the name of the disease, favism).

Many different mutations are known in the gene for glucose-6-phosphate dehydrogenase, leading to two main variants of favism. In the Afro-Caribbean variant, the enzyme is unstable, so that while average red-cell activities are low, it is only the older erythrocytes that are affected by oxidative stress, and the hemolytic crises tend to be self-limiting. By contrast, in the Mediterranean variant the enzyme is stable, but has low activity in all erythrocytes. Hemolytic crises in these people are more severe and can be fatal. Glutathione peroxidase is dependent on a supply of NADPH, which in erythrocytes can only be formed via the pentose phosphate pathway. It reduces organic peroxides and H₂O₂ as part of the body’s defense against lipid peroxidation. Measurement of erythrocyte glutathione reductase, and its activation by FAD is used to assess vitamin B2 nutritional status .

Disruption of the Uronic Acid Pathway Is Caused by Enzyme Defects & Some Drugs

 In the rare benign hereditary condition essential pentosuria, considerable quantities of xylulose appear in the urine because of a lack of xylulose reductase, the enzyme necessary to reduce xylulose to xylitol. Although pentosuria is benign, with no clinical consequences, xylulose is a reducing sugar and can give false-positive results when urinary glucose is measured using alkaline copper reagents . Various drugs increase the rate at which glucose enters the uronic acid path way. For example, administration of barbital or chlorobutanol to rats results in a significant increase in the conversion of glucose to glucuronate, l-gulonate, and ascorbate. Aminopyrine and antipyrine increase the excretion of xylulose in pentosuric subjects. Pentosuria also occurs after consumption of relatively large amounts of fruits such as pears that are rich sources of pentoses (alimentary pentosuria).

Loading of the Liver With Fructose May Potentiate Hypertriacylglycerolemia, Hypercholesterolemia, & Hyperuricemia

In the liver, fructose increases fatty acid and triacylglycerol synthesis and VLDL secretion, leading to hypertriacylglycerolemia—and increased LDL cholesterol—which can be regarded as potentially atherogenic . This is because fructose enters glycolysis via fructokinase, and the resulting fructose-1-phosphate bypasses the regulatory step catalyzed by phosphofructokinase. In addition, acute loading of the liver with fructose, as can occur with intravenous infusion or following very high fructose intakes, causes sequestration of inorganic phosphate in fructose-1-phosphate and diminished ATP synthesis. As a result, there is less inhibition of de novo purine synthesis by ATP, and uric acid formation is increased, causing hyperuricemia, which is the cause of gout. Since fructose is absorbed from the small intestine by (passive) carrier-mediated diffusion, high oral doses may lead to osmotic diarrhea.

Defects in Fructose Metabolism Cause Disease

A lack of hepatic fructokinase causes essential fructosuria, which is a benign and asymptomatic condition. The absence of aldolase B, which cleaves fructose-1-phosphate, leads to hereditary fructose intolerance, which is characterized by pro found hypoglycemia and vomiting after consumption of fructose (or sucrose, which yields fructose on digestion). Diets low in fructose, sorbitol, and sucrose are beneficial for both conditions. One consequence of hereditary fructose intolerance and of a related condition as a result of fructose 1,6-bisphosphatase deficiency is fructose-induced hypoglycemia despite the presence of high glycogen reserves, because fructose-1-phosphate and 1,6-bisphosphate allosterically inhibit liver glycogen phosphorylase. The sequestration of inorganic phosphate also leads to depletion of ATP and hyperuricemia.

Fructose & Sorbitol in the Lens Are Associated With Diabetic Cataract

Both fructose and sorbitol are found in the lens of the eye in increased concentrations in diabetes mellitus and may be involved in the pathogenesis of diabetic cataract. The sorbitol (polyol) pathway (not found in liver) is responsible for fructose formation from glucose (see Figure 1) and increases in activity as the glucose concentration rises in those tissues that are not insulin sensitive—the lens, peripheral nerves, and renal glomeruli. Glucose is reduced to sorbitol by aldose reductase, followed by oxidation of sorbitol to fructose in the presence of NAD+ and sorbitol dehydrogenase (polyol dehydrogenase). Sorbitol does not diffuse through cell mem branes, but accumulates, causing osmotic damage. Simultaneously, myoinositol levels fall. In experimental animals, sorbitol accumulation and myoinositol depletion, as well as diabetic cataract, can be prevented by aldose reductase inhibitors. A number of inhibitors are undergoing clinical trials for prevention of adverse effects of diabetes.

Fig1. Metabolism of fructose.Aldolase A is found in all tissues, whereas aldolase B is the predominant form in liver. (*Not found in liver.)

Enzyme Deficiencies in the Galactose Pathway Cause Galactosemia

 Inability to metabolize galactose occurs in the galactosemias, which may be caused by inherited defects of galactokinase, uridyl transferase, or 4-epimerase (see Figure 2A), though deficiency of uridyl transferase is best known. Galactose is a substrate for aldose reductase, forming galatitol, which accumulates in the lens of the eye, causing cataract. The condition is more severe if it is the result of a defect in the uridyl transferase since galactose-1-phosphate accumulates and depletes the liver of inorganic phosphate. Ultimately, liver failure and mental deterioration result. In uridyl transferase deficiency, the epimerase is present in adequate amounts, so that the galactosemic individual can still form UDPGal from glucose. This explains how it is possible for normal growth and development of affected children to occur despite the galactose-free diets used to control the symptoms of the disease.

Fig2. Pathway of conversion of (A) galactose to glucose in the liver and (B) glucose to lactose in the lactating mammary gland.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية يطلق باقة من النشاطات الرقمية الخاصة بشهر المحرم

العتبة العباسية المقدسة تختتم السلسلة الأولى لمشروع المحاضرات القرآنية العاشورائية في بابل

العتبة العباسية المقدسة تسلّم راية العزاء إلى تجمّع مواكب محافظة الديوانية

قسم الشؤون الفكرية يواصل إقامة المجالس الحسينية ضمن سلسلة (بيوت النعيم)

المزيد

الآخبار الصحية

لكبح الجوع وخسارة الوزن.. "سر بسيط" في نظام جوكوفيتش ؟

هل يساعد الرجيم في علاج الأمراض العقلية؟

لحماية أسنان طفلك.. هذا الفيتامين يقلل خطر التسوس

أكل الطعام بسرعة.. طريق سريع إلى أمراض خطيرة

المزيد

الآخبار التكنلوجية

ما هي أفضل درجة حرارة لتكييف الهواء في السيارة؟

ذوبان الأنهار الجليدية يوقظ "عمالقة نائمة"!

9 يوليو يشهد أقصر يوم في التاريخ المسجل ؟!!

راتبه عشرات ملايين الدولارات.. زوكربرغ يخطف "عقل أبل"

المزيد

مواضيع ذات صلة

Glycolipids (Glycosphingolipids) are Important in Nerve Tissue & in the Cell Membrane

Phospholipids are The Main Lipid Constituents of Membranes

Fatty Acids are Aliphatic Carboxylic Acids

Galactose is Needed for the Synthesis of Lactose, Glycolipids, Proteoglycans, & Glycoproteins

Ingestion of Large Quantities of Fructose has Profound Metabolic Consequences

Reactions of the Pentose Phosphate Pathway Occur in the Cytosol

Blood Glucose is Derived From the Diet, Gluconeogenesis, & Glycogenolysis

Glycolysis & gluconeogenesis share the same pathway but in opposite directions, & are reciprocally regulated

Glucose-1-Phosphate & Glycogen

Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis

Gluconeogenesis & the Control of Blood Glucose: Biomedical Importance

Glycogen Metabolism is Regulated by A Balance in Activities Between Glycogen Synthase & Phosphorylase