Other Functions of Nucleotides:- Adenine Nucleotides Are Components of Many Enzymes Cofactors
A variety of enzyme cofactors serving a wide range of chemical functions include adenosine as part of their structure (Fig. 8–41). They are unrelated structurally except for the presence of adenosine. In none of these cofactors does the adenosine portion participate directly in the primary function, but removal of adenosine generally results in a drastic reduction of cofactor activities. For example, removal of the adenine nucleotide (3-phosphoadenosine diphosphate) from acetoacetyl-CoA, the coenzyme A derivative of acetoacetate, re duces its reactivity as a substrate for -ketoacyl-CoA transferase (an enzyme of lipid metabolism) by a factor of 106. Although this requirement for adenosine has not been investigated in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and in stabilizing the initial enzyme-substrate complex (Chapter 6). In the case of-ketoacyl-CoA transferase, the nucleotide moiety of coenzyme A appears to be a binding “handle” that helps to pull the substrate (acetoacetyl-CoA) into the active site. Similar roles may be found for the nucleoside portion of other nucleotide cofactors. Why is adenosine, rather than some other large molecule, used in these structures? The answer here may involve a form of evolutionary economy. Adenosine is certainly not unique in the amount of potential binding energy it can contribute. The importance of adenosine probably lies not so much in some special chemical characteristic as in the evolutionary advantage of using one compound for multiple roles. Once ATP became the uni versal source of chemical energy, systems developed to synthesize ATP in greater abundance than the other nucleotides; because it is abundant, it becomes the logical choice for incorporation into a wide variety of structures. The economy extends to protein structure. A sin gle protein domain that binds adenosine can be used in a wide variety of enzymes. Such a domain, called a nucleotide-binding fold, is found in many enzymes that bind ATP and nucleotide cofactors.
FIGURE 8–41 Some coenzymes containing adenosine. The adenosine portion is shaded in light red. Coenzyme A (CoA) functions in acyl group transfer reactions; the acyl group (such as the acetyl or acetoacetyl group) is attached to the CoA through a thioester linkage to the -mercaptoethylamine moiety. NAD+ functions in hydride transfers, and FAD, the active form of vitamin B2 (riboflavin), in electron transfers. Another coenzyme incorporating adenosine is 5-deoxyadenosylcobalamin, the active form of vita min B12, which participates in intramolecular group transfers between adjacent carbons.
certainly not unique in the amount of potential binding energy it can contribute. The importance of adenosine probably lies not so much in some special chemical characteristic as in the evolutionary advantage of using one compound for multiple roles. Once ATP became the universal source of chemical energy, systems developed to synthesize ATP in greater abundance than the other nucleotides; because it is abundant, it becomes the logical choice for incorporation into a wide variety of structures. The economy extends to protein structure. A single protein domain that binds adenosine can be used in a wide variety of enzymes. Such a domain, called a nucleotide-binding fold, is found in many enzymes that bind ATP and nucleotide cofactors.
