Report on Allosteric Inhibition: Regulation of PFK-1 and Glycolysis

This report provides a comprehensive overview of allosteric inhibition, focusing on its role in enzyme regulation, particularly in the context of glycolysis. It explains the concept of allosteric proteins and their involvement in feedback inhibition, using phosphor-fructo-kinase-1 (PFK1) as a primary example. The report details how PFK-1, a key regulatory enzyme in glycolysis, is modulated by various allosteric effectors such as ATP, AMP, ADP, citrate, and fructose 2,6-bisphosphate. It elucidates the mechanisms by which these effectors, acting as either positive or negative regulators, influence PFK-1's activity and, consequently, the flow of glucose through the glycolytic pathway. The document references Harper's Illustrated Biochemistry and Lehninger Principles of Biochemistry to support its explanations.

Running head: ALLOSTERIC INHIBITION
Allosteric Inhibition
Name of the Student
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Author Note

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ALLOSTERIC INHIBITION
Answer 7
The term "allosteric" is derived from two Greek work, "allos" meaning "other" and
"stereos" meaning "solid". Allosteric protein aids in feedback inhibition (FI). FI is defined as
a process of enzyme inhibition in an ongoing biosynthetic pathway via the action of the end-
product of that pathway. For example biosynthesis of D from A is catalyzed via a series of
enzyme from Enz1 to Enz3. High concentration of D3 inhibits the conversion A to A. Here D
is an allosteric protein that binds to the allosteric site of the enzyme (Enz1) and thereby
modulating the catalytic site leading to enzyme inhibition. This kind of inhibition is known as
negative allosteric inhibition and D is a negative allosteric inhibitor with no structural
similarity with the A (substrate of Enz1) (Murray 2009).
Enz1 Enz2 Enz3
A B C D
Source: Murray 2009
In this report, phosphor-fructo-kinase-1 (PFK1) will be used as an example to
explain allosteric protein and enzyme inhibition mechanism. PFK-1 is the major regulatory
enzyme in the biochemical process of glycolysis. It helps in the conversion of Fructose 6-
phosphate to fructose 1,6-bisphosphate and uses pyrophosphate (PPi) and not ATP as the
phosphate group donor (Murray 2009).
Fructose 6-phosphate + PPi Fructose 1,6-bisphosphate + Pi
PFK1 + Mg 2+
Source: Murray 2009

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The activity is PFK-1 increases whenever the ATP supply of the cell is decreased or
when ATP is broken down into ADP or AMP. The action of PFK is inhibited when there is
ample supply of ATP inside the cell. Thus here high concentration of ATP (final product of
glycolysis) is acting as an allosteric inhibitor of PFK, inhibiting its effective binding with
Fructose 6-phosphate (substrate) to produce Fructose 1,6-bisphosphate. ATP inhibits PFK-1
by binding to an allosteric site and thereby lowering the affinity of PFK-1 for Fructose 6-
phosphate. On the other hand, AMP and ADP increase in concentration within the cell
whenas the utilization of ATP outpaces the production. Thus, again AMP and ADP binds
allosterically to relief the inhibition of PFK-1 as imposed by ATP. All these effects
amalgamates to generate higher enzymatic activity when AMP and ADP accumulates and on
contraty, when ATP accumulates in cell, it lowers the enzymatic activity (Murray 2009).
Citrate (an ionized from of citric acid) is a major intermediate in the aerobic oxidation
of fatty acids, pyruvate and amino acids and acts a key allosteric regulator of PFK-1. High
concentration of citrate increases the inhibitory effect of ATP on PFK. This in turn reduces
the flow of glucose through the glycolysis biochemical process. In other words, it can be said
that the citrate acts as an intracellular signal that notifies the cell that it is meeting its current
requirement for all the available energy-yielding metabolism via oxidation of fats and
proteins (Nelson, Lehninger and Cox 2008).
Fructose 2,6 bisphosphate is another allosteric effectors for PFK-1 and thus helps in
maintaining hormonal regulation of glyconeogenesis and glycolysis. Fructose 2,6-
bisphosphate binds to its allosteric site of PFK-1 and increases its (PFK-1) enzymatic affinity
towards fructose 6-phosphate and thereby reducing the effect of allosteric inhibitor (ATP) on
PFK-1. Thus Fructose 2,6-bisphosphate is positive allosteric regulator and ATP is negative
allosteric regulator of PFK-1 (Murray 2009).

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References
Murray, R.K., 2009. Harper's illustrated biochemistry (26th edition). Lange Medical
Books/McGraw-Hill; Medical Publishing Division
Nelson, D.L., Lehninger, A.L. and Cox, M.M., 2008. Lehninger principles of biochemistry.
Macmillan.

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