7: Principles and examples of metabolic regulation
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Concepts of Enzyme Regulation and Reciprocal Regulation AND Mechanisms for the Regulation of Enzymatic Reactions
Why are enzyme reactions regulated?
1. To produce products only when needed.
2. There are lots of pathways in the cell, some of which are opposing in direction (one produces a compound, the other pathway metabolizes that compound). In general, opposing pathways do not occur at the same rate, at the same time in the same cell. If they did, then no net product would be produced, but in many cases ATP and/or NADH would be consumed. When this happens, it is called complete futile cycling. Regulating enzyme activity prevents complete futile cycling and prevents the synthesis of unneeded or excess products. However, partial futile cycling is very common and useful in regulating flux.
Exceptions: heat generation, ATP hydrolysis releases energy as heat
Partial exception: having opposing steps occur at the same time allows greater control over the flux
IN GENERAL: To prevent complete futile cycling, enzymes of opposing irreversible reactions are regulated in opposite directions. This also allows greater change in flux.
How is metabolic flux regulated?
A. Regulate amount of Substrate
B. Regulate activity of Enzyme via changes in:
1. Enzyme amount (synthesis vrs degradation)
2. Type of enzyme present- (isozymes with different catalytic properties)
3. Enzyme specific activity (see below), changing activity of the same amount of enzyme.
A major mechanism of enzyme regulation is regulating enzyme specific activity
There are two main types of mechanisms for regulation of enzyme specific activity:
1 .Allostery-Enzyme activity can be activated or inhibited through non-covalent interaction of the enzyme with small molecules called effectors, modulators, or allosteric regulators (AE). Effectors bind to the enzyme at a site other than the active site (allo means other). Reversible binding to enzyme- fast response time. Concentration dependent.
2. Covalent modification- Covalent addition of a group to an enzyme changes the activity of the enzyme.
Mechanisms of Reciprocal Regulation:
To prevent complete futile cycling, regulation of enzyme activity by allostery or covalent modification works reciprocally. That is, the specific activities of one or more enzymes of a pathway are activated at the same time the specific activity of one or more enzymes of the opposing pathway is inhibited. Often the same mechanism is used (either the same modification system, or the same allosteric regulator). The same mechanism has opposite effects on enzymes of the opposing pathways.
Reciprocal regulation using allostery- Binding of the same regulator to the enzymes of opposing reactions has the opposite effect (activation for one enzyme, inhibition for the other).
Reciprocal regulation using covalent modification- The modification system modifies enzymes catalyzing opposing reactions at the same time, the same type of modification has opposite effects on the two enzymes, activating one, while inhibiting the other that operates in the opposing pathway.