Pentose Phosphate Pathway

• Ribose, fructose and galactose metabolic pathways are not grouped together due to a lack of functional relationship

Pentose Phosphate Pathway

• The pentose phosphate pathway captures energy as nicotinamide adenine dinucleotide (NADPH), a coenzyme for biosynthetic reactions
• NADPH is generated directly from NADP+
• It also serves as a de novo source of ribose for nucleotide synthesis
• It occurs entirely in the cytosol

Pathway Reaction Steps—Glucose 6-Phosphate to NADPH and Ribose

• Three reactions in the oxidative branch produce ribulose 5-phosphate (Rbl5P) and NADPH
• Glucose 6-phosphate dehydrogenase (G6PD) oxidizes glucose 6-phosphate (G6P) to 6-phosphogluconolactone while reducing NADP+ to NADPH
• A lactonase oxidizes the lactone ring to form 6-phosphogluconic acid
• 6-Phosphogluconate dehydrogenase oxidatively decarboxylates 6-phosphogluconate, yielding Rbl5P, CO2, and NADPH

Nonoxidative Branch

• In the nonoxidative branch reactions interconvert 3-, 4-, 5-, 6-, and 7-carbon sugars, producing glyceraldehyde 3-phosphate (G3P) and fructose 6-phosphate (F6P)
• Phosphopentose isomerase isomerizes Rbl5P to ribose 5-phosphate (R5P)
• Phosphopentose epimerase epimerizes Rbl5P to xylulose 5-phosphate (Xy5P)
• Transketolase (containing thiamine pyrophosphate) facilitates a 2-carbon exchange between Xy5P (5C) and R5P (5C), producing G3P (3C) and sedoheptulose 7-phosphate (7C)
• Transaldolase allows a 3-carbon exchange between G3P (3C) and sedoheptulose 7-phosphate (7C) to produce erythrose 4-phosphate (4C) and F6P (6C)
• Transketolase facilitates a 2-carbon exchange between Xy5P (5C) and erythrose 4-phosphate (4C) to produce G3P (3C) and F6P (6C)

Regulated Reactions—Glucose 6-Phosphate Dehydrogenase

• The only regulation of the pentose phosphate pathway occurs at the enzyme G6PD
• The reaction is regulated by the supply of NADP+
• NADP+ concentrations are normally very low in liver cells

Unique Characteristics—Production of NADPH or Ribose or Both

• The pentose phosphate pathway, also called the hexose monophosphate shunt, is a shunt from glycolysis designed to produce either NADPH or ribose or both
• The direction of flow of the metabolites depends on the need for the end products

Production of NADPH Only

• Tissues with the greatest pentose phosphate pathway activity have NADPH for reductive biosynthesis
• Lactating mammary glands use NADPH for fatty acid biosynthesis
• Gonads and the adrenal cortex use use NADPH for steroid hormone synthesis
• The liver also uses NADPH for fatty acid and cholesterol biosynthesis
• Red blood cells use NADPH for the reduction of glutathione (GSH)
• When NADPH only is consumed, the products of the nonoxidative branch are recycled either through reversed glycolysis to G6P or through glycolysis to pyruvate
• No energy is required to convert G3P and F6P to G6P

Production of Ribose Only

• In tissue synthesizing ribonucleic acid (RNA) or DNA actively, ribose will be pulled into pathways for the synthesis of ribonucleotides
• Fructose 6-phosphate and G3P enter the nonoxidative branch directly, bypassing G6PD, and their carbons flow through it in the reverse direction
• Xy5P is converted to R5P through its equilibrium with Rbl5P
• NADPH is not needed for RNA synthesis, but it is needed when the RNA ribose is converted to DNA deoxyribose

Production of Both NADPH and Ribose

• In a tissue undergoing active DNA synthesis, ribose is pulled into pathways for the synthesis of deoxyribonucleotides
• Thioredoxin, a cofactor in reduction of ribonucleotides to deoxyribonucleotides, requires NADPH for its regeneration
• Both NADPH and R5P are produced when G6P is routed through the oxidative branch with all carbons flowing directly to R5P, bypassing the nonoxidative branch entirely

Interface with Other Pathways—Glycolysis

• The reversible formation of glycolytic intermediates allows flow of carbon in either direction between glycolysis and the nonoxidative branch of the pathway

Related Diseases

• G6PDH Deficiency (Primaquine Sensitivity)
• GSH serves as a protective function in red blood cells by serving as a cofactor for GSH peroxidase
• This reaction neutralizes hydroperoxides, oxidizing the thiol groups in GSH
• NADPH is required for generation of the reduced form of GSH to inhibit peroxide formation
• Some drugs, such as the antimalarial quinone, primaquine, induce peroxide formation
• In patients with a deficiency in the G6PD enzyme, a damaging sequence results
• Primaquine raises the concentration of peroxides in the red blood cell
• GSH peroxidase acts to neutralize the peroxides, creating oxidized GSH
• Oxidized GSH remains in the oxidized form because of the lack of NADPH
• Reduced GSH is depleted, allowing the peroxide radicals to attack cellular components
• The weakened cell membranes break, and the red blood cells lyse, a condition called hemolysis

Histology

• Patients with G6PD deficiency have Heinz bodies in their red blood cells
• Heinz bodies are clumps of denatured hemoglobin resulting from exposure to high oxidant levels that oxidize sulfhydryl groups on adjacent molecules, joining them with a covalent disulfide bond
• The oxidation process may cause enough damage to the erythrocyte plasma membrane to result in hemolysis

Microbiology

• Oxidant stress on red blood cells can come from internal and external sources
• During infection, the activated neutrophils and macrophages create superoxide and peroxide radicals to kill the infectious agents
• Exposure to these active O2 species will also lead to hemolysis in a G6PD-deficient red blood cell

Pharmacology

• Dapsone, a drug used to treat Mycobacterium leprae infection in leprosy patients and Pneumocystis jiroveci infections in AIDS patients, can induce hemolytic anemia in those patients through the production of peroxides and the subsequent oxidation damage
• In patients who have G6PD deficiency, the incidence of hemolytic anemia is approximately doubled owing to the depletion of GSH

Galactose Metabolism

• Galactose is supplied in the diet from dairy products that contain the disaccharide lactose
• Digestion of lactose produces glucose and galactose, both of which are transported through the hepatic portal vein directly to the liver
• Galactose is metabolized by conversion initially to glucose 1-phosphate (G1P), which can then be converted either to G6P or to glycogen

Pathway Reaction Steps—Galactose to Glucose 1-Phosphate

• Galactokinase phosphorylates galactose with ATP to produce galactose 1-phosphate (Gal1P)
• Galactose 1-phosphate uridyl-transferase exchanges Gal1P with uridine diphosphate (UDP)-glucose to produce UDP-galactose and G1P
• Uridine diphosphate-galactose 4-epimerase converts UDP-galactose to UDP-glucose, which can then undergo the transferase reaction again

Regulated Reactions—No Regulation

• There is no known regulated step in the conversion of galactose to glucose intermediates
• The fate of glucose from dietary galactose, toward either glycolysis or glycogenesis, is determined by pathways regulating glucose metabolism in the liver

Unique Characteristics—Uridine Diphosphate-Glucose Intermediate

• Although the galactose pathway forms UDP-glucose, there is no net synthesis of this intermediate, since it is recycled
• The net output of this pathway is the conversion of a mole of Gal1P to G1P

Interface with Other Pathways—Polyol Pathway

• Free galactose can be reduced by aldose reductase in the polyol pathway to galactitol
• The polyol pathway is widely distributed in the body including in the lens, where it contributes to the formation of cataracts in both galactosemia and diabetes

Related Diseases

• Deficiencies in galactose pathway enzymes produce a disease called galactosemia, since they lead to an elevation in blood galactose concentration
• Classic galactosemia results from a deficiency in Gal1P-uridyl-transferase, and accumulation of both galactose and Gal1P
• Gal1P is cytotoxic in blood and tissues, and produces liver and neural damage
• Galactose is also converted to galactitol by aldose reductase
• Accumulation of galactitol in the lens causes osmotic and oxidative stress, leading to cataracts as a result of denaturation and precipitation of lens crystallin
• A secondary form of galactosemia results from a deficiency in galactokinase
• Since the toxic Gal1P does not increase, there is no liver or neural damage, but the patients nevertheless develop cataracts owing to the elevated blood galactose
• Diabetic patients with chronically poor glycemic control may also develop cataracts
• In this case, the increased blood glucose leads to an increased activity of the polyol pathway with the production of sorbitol

Fructose Metabolism

• Fructose is supplied in the diet from fruits, sucrose (table sugar), and honey
• Digestion of sucrose produces glucose and fructose, both of which are transported through the hepatic portal vein directly to the liver
• The fructose is then metabolized in a modified pathway similar to the first half of glycolysis to produce intermediates that then enter the last half of glycolysis

Pathway Reaction Steps—Fructose to Dihydroxyacetone Phosphate and Glyceraldehyde

• Fructokinase phosphorylates Fructose with ATP to produce fructose 1-phosphate (F1P)
• Fructose 1-phosphate aldolase (aldolase B) Aldol cleavage of F1P produces dihydroxyacetone phosphate and glyceraldehyde
• Triose kinase phosphorylates Glyceraldehyde from ATP to produce G3P

Fructose Synthesis

• Fructose is produced from glucose through the polyol pathway in the seminal vesicles, which serves as the primary energy source for spermatozoa
• No Regulation for Fructose

Regulated Reactions—No Regulation

• Fructose metabolism bypasses the normal phosphofructokinase regulation of glycolysis and can accelerate fat synthesis

Unique Characteristics—Aldolase B Specificity

• Fructokinase, like glucokinase, is found primarily in the liver
• Unlike hexokinase and glucokinase, it phosphorylates the sugar at the C-1 position
• Aldolase B, which is specific to the liver, works on both F1,6-BP and F1P
• In extrahepatic tissues such as muscle or adipose tissue, fructose is phosphorylated to F6P by hexokinase

Interface with Other Pathways—Amino Sugars in Glycoproteins and Glycolipids

• F6P is a precursor for amino sugars in glycoproteins and glycolipids

Related Diseases

• Hereditary Fructose Intolerance- A deficiency in aldolase B produces hereditary fructose intolerance
• The increase in F1P results in liver and kidney damage comparable to that seen with increased Gal1P in galactosemia

Essential Fructosuria

• A deficiency of fructokinase produces a benign condition marked only by an increase in fructose in the blood and urine