The activity of many enzymes is regulated by the noncovalent binding of small molecules known as effectors. Effector binding can modulate enzyme function by virtue of the fact that the enzyme–effector complex is a distinct molecular entity from the individual enzyme and effector molecules, and thus can manifest properties different than those of its separated components. Effector binding can increase (activate) or decrease (inhibit) the catalytic efficiency of the target enzyme, cause it to translocate to a different location within a cell, trig ger its association with (or dissociation) from other proteins, or even potentiate or suppress sensitivity to the binding of a second effector or to covalent modification. Physiologic effectors include several of the end products and intermediates of key metabolic pathways, as well as specialized biomolecules whose sole function is to act as regulatory ligands.

Most effectors bear little or no resemblance to the substrates or products of the affected enzyme. For example an effector of 3-phosphoglycerate dehydrogenase, the amino acid serine, displays minimal structural overlap with either of the enzyme’s substrates, 3-phosphoglycerate and NAD⁺ (Figure 1). Jacques Monod reasoned that the lack of structural similarity between most physiologic effectors and the reactants targeted for catalytic transformation by their cognate enzymes indicated that these modulators bound at a site that was physically distinct and perhaps even physically distant from an enzyme’s active site. Monod employed the term allosteric, which means to “occupy another space,” to classify these modulatory sites as well as the effectors that are bound to them. The ability of allosteric ligands to influence events taking place at the active site can be attributed to their ability to induce conformational changes that affect all or large portions on an enzyme. Allosteric effectors may influence catalytic efficiency by altering the K_m for a substrate (K series allosteric enzymes), V_max (V-series allosteric enzymes), or both.

Fig1. Serine regulates its rate of synthesis by acting as a feedback inhibitor. Shown are the three enzyme-catalyzed reactions by which the amino acid serine is synthesized from the glycolytic intermediate, glyceraldehyde 3-phosphate. The red arrow indicates that serine binds to 3-phosphoglycerate dehydrogenase, inhibiting the enzyme’s activity (symbolized by the red “X”). Through this simple mechanism, when cellular demand for serine, the pathway end product, declines and its concentration begins to increase, serine synthesis is reduced by its action as a feedback inhibitor of the enzyme responsible for catalyzing the first committed step in the pathway.

Allosteric Effectors Can Be Grouped Into Three Functional Classes

Allosteric effectors can be classified into three categories based on their origin and scope of action. Feedback effectors are pathway end products or intermediates that bind to and either activate or inhibit one or more enzymes within the pathway responsible for their synthesis. In most cases, feedback inhibitors bind to the enzyme that catalyzes the first committed step in a particular biosynthetic sequence. In the following example, the biosynthesis of D from A is catalyzed by enzymes Enz₁ through Enz₃ :

Enz₁ Enz₂ Enz₃

A→B→C→D

In the case of 3-phosphoglycerate dehydrogenase, serine is the end product of a pathway for which this enzyme catalyzes the first committed step (see Figure 1).

The regulatory function of feedback effectors is secondary in importance to their role metabolism. Their scope of action is also localized to the pathway responsible for their synthesis. In most cases, the binding of an end product or intermediate decreases the catalytic efficiency of their enzyme target, a pat tern called feedback inhibition.

Like feedback effectors, indicator metabolites also are metabolic end products or intermediates with a secondary role as allosteric effectors of enzymes. They are distinguished from feedback effectors by their scope of action, which extends beyond or even lies outside of their pathway of origin. This enables indicator metabolites to coordinate flux through multiple metabolic pathways. For example, citrate—a key intermediate in the citric acid cycle —acts as an allosteric activator of the enzyme responsible for catalyz ing the first committed step in fatty acid biosynthesis, acetyl CoA carboxylase , while alanine acts as an allosteric inhibitor of the glycolytic enzyme pyruvate kinase .

Unlike indicator metabolites or feedback effectors, second messengers are specialized allosteric ligands whose production or release is triggered in response to an external first messenger, such as a hormone or nerve impulse. Some typical second messengers include 3′, 5′-cAMP, synthesized from ATP by the enzyme adenylyl cyclase in response to the hormone epinephrine, and Ca2+, which is stored inside the endoplasmic reticulum of most cells. Membrane depolarization resulting from a nerve impulse opens a membrane channel that releases calcium ions into the cytoplasm, where they bind to and activate enzymes involved in the regulation of muscle contraction and mobilize stored glucose from glycogen by binding to and activating phosphorylase kinase. Other second messengers include 3′,5′-cGMP, nitric oxide, and the polyphosphoinositols produced by the hydrolysis of inositol phospholipids by hormone-regulated phospholipases.

مواضيع ذات صلة

Regulatory Covalent Modifications can be Reversible or Irreversible

الأهمية الحيوية الطبية للأنزيمات

انزیم ( Glutamate Pyruvate Transaminase or Alanine Transaminas) GPT or ALT

أنزيم GOT ( AST ) (Glutamate Oxaloacetate Transaminase or Aspartate Transaminase)

كيف يعمل الأنزيم

فرضية القفل والمفتاح Lock and Key hypothesis

تصنيف الانزيمات Classification of Enzymes

الانزيمات Enzymes

Initial Considerations and Primary Recovery

Applications of Immobilisation

Coenzyme Regeneration

Catalytic Activity