Question

Gout is a disease in which uric acid is high in blood and urine. One patient who excreted three times normal uric acid had very high blood levels of PRPP, an intermediate in biosynthesis of AMP and GMP, which are precursors of ATP and GTP. Degradation of these products produces uric acid. The patient's PRPP synthetase had normal \(K_{m}\) and \(V_{\max }\) values but was insensitive to regulation by the end products of the pathway (ATP, GTP). These are negative allosteric modifiers of PRPP synthetase. All of the following statements about allosteric effectors are correct except they A. may increase the enzyme's affinity for its substrate. B. may decrease the enzyme's affinity for its substrate. C. bind at the substrate binding site. D. cause a conformational change in the enzyme. E. can change either the \(K_{m}\) or the \(V_{\max }\) of the reaction.

Short answer

Answer: C. Allosteric effectors bind at the substrate binding site.

Step-by-step solution

Statement A: Allosteric effectors may increase the enzyme's affinity for its substrate.

This is a correct statement as allosteric effectors, when binding to the enzyme at a site distinct from the substrate binding site, can induce conformational changes in the enzyme which can result in an increased affinity for its substrate.

Statement B: Allosteric effectors may decrease the enzyme's affinity for its substrate.

This is also a correct statement because, as mentioned earlier, allosteric effectors can cause conformational changes in the enzyme, which can ultimately lead to reduced affinity for its substrate. This is usually the case when an allosteric inhibitor binds to the enzyme.

Statement C: Allosteric effectors bind at the substrate binding site.

This statement is incorrect. Allosteric effectors do not bind at the substrate binding site of the enzyme. Instead, they bind to a site different from the substrate binding site. This distinct site is termed as the allosteric site.

Statement D: Allosteric effectors cause a conformational change in the enzyme.

This statement is correct. As discussed earlier, the binding of allosteric effectors at the allosteric site causes conformational changes in the enzyme, which can affect its activity or its affinity for the substrate.

Statement E: Allosteric effectors can change either the \(K_{m}\) or the \(V_{\max }\) of the reaction.

This statement is correct. The conformational changes induced by allosteric effectors in the enzyme can lead to alterations in enzyme kinetics, which can be reflected as changes in either the \(K_{m}\) (substrate concentration required to reach half-maximal velocity) or the \(V_{\max }\) (maximum velocity) of the reaction. Based on the analysis, the incorrect statement about allosteric effectors is: C. Allosteric effectors bind at the substrate binding site.

Key concepts

Enzyme Kinetics

Enzyme kinetics is a fundamental concept in biochemistry that focuses on how enzymes bind to substrates and turn them into products.
The rate at which this happens is referred to as the reaction velocity. To understand this process more clearly, two parameters are often discussed: the Michaelis constant (\(K_{m}\)) and the maximum velocity (\(V_{\text{max}}\)).

The Michaelis constant (\(K_{m}\)) is a measure of the substrate concentration required for an enzyme to reach half of its maximum velocity. A low \(K_{m}\) indicates high enzyme affinity for the substrate, meaning the enzyme can achieve half of its \(V_{\text{max}}\) even at low substrate concentrations. Conversely, a high \(K_{m}\) suggests a lower affinity, which necessitates a higher substrate concentration to reach half of \(V_{\text{max}}\).

The maximum velocity (\(V_{\text{max}}\)), on the other hand, is a theoretical maximum rate of the reaction, which assumes all enzyme active sites are bound with substrate. These concepts are crucial for understanding enzyme behavior and designing drugs that target enzyme activity.

PRPP Synthetase Regulation

The regulation of PRPP synthetase plays a key role in nucleotide biosynthesis and energy metabolism, which ultimately impacts the production of uric acid — the compound associated with gout.

PRPP synthetase is subject to feedback inhibition, a regulatory mechanism where the end products of a pathway inhibit an earlier enzyme in the pathway to maintain homeostasis. In the context of PRPP synthetase, molecules such as ATP and GTP serve as negative allosteric effectors. They bind to the allosteric sites on the enzyme and not the active site, as some may incorrectly assume.

Effects of Allosteric Regulation

When these effectors bind, they alter the enzyme's conformation, leading to a decreased affinity for its substrate; this can prevent overproduction of nucleotides and subsequent excess uric acid. However, if PRPP synthetase becomes insensitive to these negative effectors, as was the case with the patient mentioned in the exercise, the production of PRPP is not adequately regulated, potentially leading to hyperuricemia and gout.

Biochemistry of Gout

Gout is a form of inflammatory arthritis characterized by elevated levels of uric acid in the blood, a condition known as hyperuricemia. Uric acid is a waste product usually excreted by the kidneys.

When uric acid accumulates, it can form crystals in the joints, causing intense pain and swelling — a classic symptom of gout. Uric acid is the end product of purine metabolism; purines are derived from the diet and from the natural breakdown of cells in the body.

Contributing Factors to Gout

Factors that contribute to gout include dietary choices, alcohol consumption, certain medications, and genetics. Understanding the biochemistry of gout, including the regulatory role of enzymes like PRPP synthetase in purine metabolism, allows for better management of the condition through lifestyle adjustments or medications designed to manage uric acid levels in the body.