Unit 14 Question Bank
1. The formation of NADPH for the synthesis of fatty acids and steroids.
2. The synthesis of ribose for nucleotide and nucleic acid formation.
Oxidation is by dehydrogenation, but NADP⁺ and not NAD⁺ is the hydrogen acceptor. It has an oxidative, non-reversible phase (glucose 6-phosphate → ribulose 5-phosphate, yielding 2 NADPH and CO₂) and a non-oxidative, reversible phase (ribulose 5-phosphate back to glucose 6-phosphate, mainly via transketolase and transaldolase).
It is called a shunt because it begins with the glycolytic intermediate glucose 6-phosphate and rejoins glycolysis at glyceraldehyde 3-phosphate and fructose 6-phosphate.TMU “Chapter 20” Slides 2, 4, 10 · Harper's ch.20
Mechanism: without G6PD the erythrocyte cannot make NADPH; glutathione reductase (a flavoprotein containing FAD) therefore cannot regenerate reduced glutathione; glutathione peroxidase (which contains selenocysteine at its active site) cannot remove H₂O₂; and accumulating peroxide causes oxidative damage to the cell membrane, decreasing the life span of the erythrocyte and leading to haemolysis.
The erythrocyte is uniquely vulnerable because it has no other source of NADPH and no nucleus with which to make more enzyme.TMU “Chapter 20” Slides 8, 16
It is of major significance for the excretion of metabolites and foreign chemicals (xenobiotics) as glucuronides — the biochemical basis of hepatic drug conjugation. A deficiency in the pathway leads to essential pentosuria.TMU “Chapter 20” Slide 8
Definition and functions
The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not generate ATP, but has two major functions: the formation of NADPH for the synthesis of fatty acids and steroids, and the synthesis of ribose for nucleotide and nucleic acid formation.
Location and the “shunt”
The enzymes, as of glycolysis, are cytosolic. The pathway begins with the glycolytic intermediate glucose 6-phosphate and reconnects with glycolysis, since two of its end products — glyceraldehyde 3-phosphate and fructose 6-phosphate — are intermediates further down that pathway. It is for this reason that it is called a shunt.
Overall, three molecules of glucose 6-phosphate give rise to three molecules of CO₂ and three five-carbon sugars, rearranged to regenerate two glucose 6-phosphate and one glyceraldehyde 3-phosphate.
The two phases
Oxidative, non-reversible. Glucose-6-phosphate dehydrogenase, an NADP-dependent enzyme, dehydrogenates glucose 6-phosphate to 6-phosphogluconolactone, hydrolysed by gluconolactone hydrolase to 6-phosphogluconate. 6-Phosphogluconate dehydrogenase, also NADP⁺-requiring, then carries out decarboxylation followed by formation of the ketopentose ribulose 5-phosphate. This phase yields 2 NADPH and CO₂.
Non-oxidative, reversible. Ribulose 5-phosphate 3-epimerase forms xylulose 5-phosphate; ribose 5-phosphate ketoisomerase forms ribose 5-phosphate, the precursor of the ribose required for nucleotide synthesis. Transketolase and transaldolase then rearrange the carbon skeletons back to glucose 6-phosphate.
Distinction from glycolysis
Although glucose 6-phosphate is common to both, oxidation utilises NADP rather than NAD; CO₂, which is not produced in glycolysis, is a characteristic product; and no ATP is generated.
Biomedical importance
The pathway is active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis and lactating mammary gland, and low in non-lactating mammary gland and skeletal muscle. These tissues use NADPH in reductive syntheses — of fatty acids, steroids, amino acids via glutamate dehydrogenase, and reduced glutathione. The two dehydrogenases may be induced by insulin in the fed state, when lipogenesis increases.
Genetic deficiency of glucose-6-phosphate dehydrogenase is a major cause of haemolysis of red blood cells, resulting in haemolytic anaemia and affecting approximately 100 million people worldwide. Separately, glucuronic acid is synthesised from glucose via the uronic acid pathway, of major significance for the excretion of metabolites and xenobiotics as glucuronides; a deficiency leads to essential pentosuria.
The problem the erythrocyte faces
The erythrocyte is, by profession, the most oxidatively stressed cell in the body — it carries oxygen continuously. Yet it has no mitochondria, no nucleus with which to synthesise fresh enzyme, and no other source of NADPH. It also synthesises nothing, so its need for NADPH is not for biosynthesis at all but purely for antioxidant defence.
The protective chain
- The pentose phosphate pathway provides NADPH. The oxidative phase — glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, both NADP-dependent — yields two molecules of NADPH per glucose 6-phosphate.
- Glutathione reductase, a flavoprotein containing FAD, uses that NADPH to reduce oxidised glutathione.
- Reduced glutathione removes H₂O₂, in a reaction catalysed by glutathione peroxidase, an enzyme that contains the selenium analogue of cysteine — selenocysteine — at its active site.
This last point connects to the classification of the amino acids: selenocysteine is the 21st protein amino acid, and glutathione peroxidase is one of its principal uses in the human body — which is also why selenium is an essential dietary trace element.
Why removing H₂O₂ matters
Accumulation of H₂O₂ may decrease the life span of the erythrocyte by causing oxidative damage to the cell membrane, leading to haemolysis. The red cell has no capacity to repair or replace damaged membrane protein, so oxidative injury is cumulative and terminal.
What happens when the chain breaks — G6PD deficiency
Genetic deficiency of glucose-6-phosphate dehydrogenase, the first enzyme of the pentose phosphate pathway, is a major cause of haemolysis of red blood cells, resulting in haemolytic anaemia and affecting approximately 100 million people worldwide.
The mechanism follows the chain in reverse: no G6PD → no NADPH → glutathione reductase cannot regenerate reduced glutathione → glutathione peroxidase cannot remove H₂O₂ → peroxide accumulates → oxidative damage to the membrane → haemolysis.
G6PD is the appropriate site for such a defect to matter because it is the first enzyme of the irreversible oxidative phase, and therefore the committed, rate-limiting step — there is no route around it.
Clinical corollary
Because the defect only manifests under oxidative load, haemolysis in G6PD deficiency is typically episodic, precipitated by oxidant drugs, infection or certain foods, rather than continuous. Compare the analogous logic in sickle cell disease, where polymerisation requires the deoxygenated T state, and the crisis is likewise precipitated rather than constant.