Sunday, 27 April 2014

More thoughts on interactions

Before I leave our discussion of fertilisation, here are a few more thoughts on molecular interactions. In particular think about the way proteins are drafted in to bring cells together, compared with the way in which small molecules interact with enzyme active sites. It is instructive to consider the interaction of an enzyme with its substrate. What is the normal concentration ratio between a metabolic enzyme (for example) and its substrate? It will of course vary, but I would expect it is often 1000:1 (substrate concentration to enzyme). Take a glycolytic enzyme such as hexokinase which activates six-carbon sugars for entree into the energy generating pathway of glycolysis. 

Hexokinase requires ATP (a common source of phosphate) and glucose to come together in the correct orientation at the active site of the enzyme. At this point there will be one molecule of each: enzyme, sugar and ATP. Recall that in the case of an interaction between two molecules (A and B) the on rate is largely determined (in Biology) by diffusion through an aqueous medium. Therefore, you might expect the correct spatial encounter between 3 molecules to be less frequent than between 2. What I want to point out is that the next stage, in which one or more chemical steps take place, can sometimes be broken down into stages (one of the ways we think enzymes achieve catalysis). The total conversion (in this case) of the two substrates into glucose-6-phosphate and ADP, may not be achieved after every three way encounter. In other words productive interaction may not be 100% efficient (in fact we know that so called abortive complexes form at the active sites of many enzymes). This is not dissimilar to the case of sperm egg recognition. 

We should consider molecular encounters as a series of phased processes that sometimes lead to a productive outcome: a sugar phosphate in the case of hexokinase, or a fertilised egg in the case of Reproductive Biology. But sometimes the pathway is aborted or diverted and in some cases enzymes can give rise to alternative outcomes. The evolutionary pressures that are brought to bear on molecular interactions are therefore not just simply those that ensure specificity and affinity of encounter: sometimes downstream consequences form part of the story. I shall return to this when we consider the landmark experiments on the proteases and the enzymes that ensure the correct amino acids are added to growing protein chains: the aminoacyl tRNA synthetases, which have informed a great deal of our thinking on enzyme mechanism. But for now, think about thermodynamics in the context of evolution when rationalizing new discoveries, such as sperm egg recognition.

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