MCAT Biochemistry Review
Chapter 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis, and the Pentose Phosphate Pathway
9.7 The Pentose Phosphate Pathway
The pentose phosphate pathway (PPP), also known as the hexose monophosphate (HMP) shunt, occurs in the cytoplasm of all cells, where it serves two major functions: production of NADPH and serving as a source of ribose 5-phosphate for nucleotide synthesis.
An abbreviated diagram of the pathway is shown in Figure 9.13. The first part of the PPP begins with glucose 6-phosphate, ends with ribulose 5-phosphate, and is irreversible. This part produces NADPH and involves the important rate-limiting enzyme glucose-6-phosphate dehydrogenase(G6PD). G6PD is induced by insulin because the abundance of sugar entering the cell under insulin stimulation will be shunted into both fuel utilization pathways (glycolysis and aerobic respiration) as well as fuel storage pathways (fatty acid synthesis, glycogenesis, and the PPP). The shunt is also inhibited by its product, NADPH, and is activated by one of its reactants, NADP+.
Figure 9.13. The Pentose Phosphate Pathway
G6PD deficiency is an X-linked disorder and is the most common inherited enzyme defect in the world. Because the PPP is critically important in maintaining levels of glutathione, which helps break down peroxides, these individuals are susceptible to oxidative stress, especially in red blood cells, which carry a large concentration of oxygen. Ingestion of certain oxidizing compounds (especially particular antibiotics and antimalarial medications) or infections can lead to high concentrations of reactive oxygen species, which cause red blood cell lysis. It is hypothesized that the defect evolved because it provides some resistance to malaria infection. G6PD deficiency has also been called favism because fava beans are a highly oxidizing food that will also cause hemolysis in these individuals.
The second part of the pathway, beginning with ribulose 5-phosphate, represents a series of reversible reactions that produce an equilibrated pool of sugars for biosynthesis, including ribose 5-phosphate for nucleotide synthesis. Because fructose 6-phosphate and glyceraldehyde 3-phosphate are among the sugars produced, intermediates can feed back into glycolysis; conversely, pentoses can be made from glycolytic intermediates without going through the G6PD reaction. These interconversions are primarily accomplished by the enzymes transketolase and transaldolase.
The ribulose 5-phosphate created in the PPP is isomerized to ribose 5-phosphate, the backbone of nucleic acids. When coupled to a nitrogenous base, it forms a nucleotide that can be integrated into RNA. Make sure to review RNA synthesis (transcription; Chapter 7 of MCAT Biochemistry Review), as well as DNA synthesis (Chapter 6 of MCAT Biochemistry Review) because these are highly tested topics on the MCAT.
FUNCTIONS OF NADPH
While their names appear similar, NADPH and NADH are not the same thing. In the cell, NAD+ acts as a high-energy electron acceptor from a number of biochemical reactions. It thus can be thought of as a potent oxidizing agent because it helps another molecule be oxidized (and thus is reduced itself during the process). The NADH produced from this reduction of NAD+ can then feed into the electron transport chain to indirectly produce ATP.
NADPH and NADH are not the same thing. NAD+ is an energy carrier; NADPH is used in biosynthesis, in the immune system, and to help prevent oxidative damage.
Conversely, NADPH primarily acts as an electron donor in a number of biochemical reactions. It thus can be thought of as a potent reducing agent because it helps other molecules be reduced (and thus is oxidized itself during the process). Cells require NADPH for a variety of functions, including:
· Biosynthesis, mainly of fatty acids and cholesterol
· Assisting in cellular bleach production in certain white blood cells, thereby contributing to bactericidal activity
· Maintenance of a supply of reduced glutathione to protect against reactive oxygen species (acting as the body's natural antioxidant)
This last function is important in protecting cells from free radical oxidative damage caused by peroxides. Hydrogen peroxide, H2O2, is produced as a byproduct in aerobic metabolism, and can break apart to form hydroxide radicals, OH•–. Free radicals can attack lipids, including those in the phospholipids of the membrane. When oxidized, these lipids lose their function and can weaken the membrane, causing cell lysis. This is especially true in red blood cells, which contain high levels of oxygen, which, when oxidized by other free radicals, becomes the superoxide radical O2•–. Free radicals can also damage DNA, potentially causing cancer. Glutathione is a reducing agent that can help reverse radical formation before damage is done to the cell.
MCAT Concept Check 9.7:
Before you move on, assess your understanding of the material with these questions.
1. What are the two major metabolic products of the pentose phosphate pathway (PPP)?
2. What are three primary functions of NADPH?