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Wehave seen that an unfavorable equilibrium can be overcome by coupling such a reaction to one with a favorable equilibrium, such as thehydrolysis of an anhydride. Pyrophosphate would be just as effective asATP in its potential effects on reaction equilibria. Therefore, the advantage to cells in using ATP rather than pyrophosphate must lie inreaction rates. In Chapter 8 we described how the energy used in catalysis is derived from binding energy, the multiple weak interactionsthat occur between substrate and enzyme.
ATP, because of its largerstructure, clearly can contribute many more of these weak interactionsthan pyrophosphate. In other words, the potential for reaction rateenhancement is much greater for ATP than pyrophosphate. A reactionwith a favorable energetic equilibrium will not be of benefit to a cell ifit takes several years to occur. This principle can be illustrated by thesimple empirical observation that pyrophosphate will rarely functionin an enzymatic reaction requiring ATP, even though it should fit intoany enzyme active site that can accommodate ATP.Chapter 12 Nucleotides and Nucleic Acids353Nucleotides Are Components of Many Enzyme CofactorsA variety of enzyme cofactors serving a wide range of chemical functions include adenosine as part of their structure (Fig. 12-41). They areunrelated structurally except for the presence of adenosine.
In none ofthese cofactors does the adenosine portion participate directly in theprimary function, but removal of adenosine from these structures generally results in a drastic reduction of their activities. For example,removal of the adenosine nucleotide (3'-P-ADP; see Fig.
12-41) fromacetoacetyl-CoA reduces its reactivity as a substrate for /3-ketoacylCoA transferase (an enzyme of lipid metabolism) by a factor of 106.Although the reason for this requirement for adenosine has not beenexamined in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and tostabilize the initial ES complex (Chapter 8). In the case of CoA transferase, the nucleotide appears to be a binding "handle" that helps toHH CH 3HFigure 12—41 Enzyme cofactors and coenzymesincorporating adenosine in their structure.
Theadenosine portion is shaded in red. Coenzyme Afunctions in acyl group transfer reactions; NAD~participates in hydride transfers; FAD, the activeform of vitamin B2 (riboflavin), participates in electron transfers. Another coenzyme incorporatingadenosine in its structure is 5'-deoxyadenosylcobalamin, the active form of vitamin B12 (see Box16-2). This coenzyme is involved in intramoleculargroup transfers between adjacent carbons.O"IHS—CH2 —CH2 —N—C—CH2 —CH2 —N—C—C—C—CH2 —O—P—O—P—O—CH2iOLj3-MercaptoethylamineO OHCH,OOPantothenic acidCoenzyme A3'-Phosphoadenosine diphosphate(3'-P-ADP)CHO^ -C-NH2I NicotinamideRiboflavinOOOH OHOH OH+Nicotinamide adenine dinucleotide (NAD )Flavin adenine dinucleotide (FAD)Part II Structure and Catalysispull the substrate into the active site. Similar roles may be found fatthe nucleoside portion of other nucleotide cofactors.Now we may ask why adenosine, rather than some other largimolecule, is used in these structures.
The answer here may involve Ikind of evolutionary economy. Adenosine is certainly not unique in thfamount of potential binding energy it can contribute. The important*of adenosine probably lies not so much in some special chemical chaftacteristic, but rather that an advantage existed in making one com*pound a standard. Once ATP became the standard source of chemicalenergy, systems developed to synthesize ATP more efficiently than tteother nucleotides; because it is abundant, it becomes the logical choicifor incorporation into a wide variety of structures. The economy ex*tends to protein structure. A protein domain that binds adenosine canbe used in a wide variety of different enzymes.
Such a structure, calleda nucleotide-binding fold, is found in many enzymes that bind ATP.and nucleotide cofactors.Some Nucleotides Are Intermediates inCellular CommunicationCells respond to their environment by taking cues from hormones orother chemical signals in the surrounding medium. The interaction ofthese extracellular chemical signals (first messengers) with receptorson the cell surface often leads to the production of second messengers inside the cell, which in turn lead to adaptive changes in the cellinterior (Chapter 22). Often, the second messenger is a nucleotide.One of the most common second messengers is the nucleotideadenosine 3',5'-cyclic monophosphate (cyclic AMP, or cAMP),formed from ATP in a reaction catalyzed by adenylate cyclase, associated with the inner face of the plasma membrane.
Cyclic AMP serves*regulatory functions in virtually every cell outside the plant kingdom,and these are described in detail in Chapter 22. Guanosine 3',5'-cydicmonophosphate (cGMP) occurs in many cells and also has regulatoryfunctions.Another regulatory nucleotide, ppGpp, is produced in bacteria inresponse to the slowdown in protein synthesis that occurs duringamino acid starvation.
This nucleotide inhibits the synthesis of therRNA and tRNA molecules (Chapter 27) needed for protein synthesis,preventing the unnecessary production of nucleic acids.O"IO"I5'O-P-O-P-O-CH2OOGuanineOHosine 3',5'-cyclic monophosphate(cyclic AMP; cAMP)O=PO OHO"Guanosine 3',5'-cyclic monophosphate(cyclic GMP; cGMP)Guanosine 3'-diphosphate,5'-diphosphate(guanosine tetraphosphate)(ppGpp)Chapter 12 Nucleotides and Nucleic Acids355SummaryNucleotides serve a diverse set of important functions in cells.
As subunits of nucleic acids theycarry genetic information. They are also the primary carriers of chemical energy in cells, structural components of many enzyme cofactors, andcellular second messengers.A nucleotide consists of a nitrogenous base (purine or pyrimidine), a pentose sugar, and one ormore phosphate groups. Nucleic acids are polymers of nucleotides, linked together by phosphodiester bridges between the 5' hydroxyl of one pentose and the 3' hydroxyl of the next. There are twotypes of nucleic acid: RNA and DNA. The nucleotides in RNA contain ribose, and the common pyrimidine bases are uracil and cytosine. In DNA,the nucleotides contain 2'-deoxyribose, and thepyrimidine bases are generally thymine and cytosine.
The primary purines are adenosine and guanine in both RNA and DNA.Many lines of evidence show that DNA bearsgenetic information. In particular, the AveryMacLeod-McCarty experiment showed that DNAisolated from one strain of a bacterium can enterand transform the cells of another strain, endowing it with some of the inheritable characteristicsof the donor. The Hershey-Chase experimentshowed that the DNA of a bacterial virus, but notits protein coat, carries the genetic message forreplication of the virus in the host cell.From x-ray diffraction studies of DNA fibersand the base equivalences in DNA discovered byChargaff (A = T and G = C), Watson and Crickpostulated that native DNA consists of two antiparallel chains in a right-handed double-helicalarrangement. Complementary base pairs, A=Tand G=C, are formed by hydrogen bonding withinthe helix, and the hydrophilic sugar-phosphatebackbones are located on the outside.
The basepairs are stacked perpendicular to the long axis,0.34 nm apart; there are about 10 base pairs ineach complete turn of the double helix.DNA can exist in several structural forms. Twovariations from the Watson-Crick B-form DNA,the A and Z forms, have been characterized inDNA crystal structures. The A-form helix isshorter and of greater diameter than a B-formhelix with the same sequence. The Z form is a lefthanded helix. Some sequence-dependent structural variations cause bends in the DNA. DNAstrands with self-complementary inverted repeatscan form hairpin or cruciform structures.Polypyrimidine tracts arranged in mirror repeatscan take up a triple-helical structure calledH-DNA.Messenger RNA is the vehicle by which geneticinformation is transferred to ribosomes for proteinsynthesis.
Transfer RNA and ribosomal RNA arealso involved in protein synthesis. RNA can bestructurally complex, with single RNA strandsoften folded into hairpins, double-stranded regions, and complex loops.Native DNA undergoes reversible unwindingand separation (melting) of strands on heating orat extremes of pH. Because G=C base pairs aremore stable than A=T pairs, the melting point ofDNAs rich in G=C pairs is higher than that ofDNAs rich in A=T pairs.
Denatured singlestranded DNAs from two species can form a hybridduplex, the degree of hybridization depending onthe extent of sequence homology. Hybridization isthe basis for important techniques used to studyand isolate specific genes and RNAs.DNA is a relatively stable polymer. Very slow,spontaneous reactions such as deamination of certain bases, hydrolysis of base-sugar A^-glycosidicbonds, formation of pyrimidine dimers (radiationdamage), and oxidative damage are important because of the very low tolerance of cells for changesin genetic material. DNA sequences can be determined and DNA polymers synthesized using simple protocols involving chemical and enzymaticmethods.ATP is the central carrier of chemical energy incells, probably reflecting the requirement for binding energy in catalysis.
The presence of adenosinein the structure of a variety of enzyme cofactorsmay also be related to binding energy requirements. Cyclic AMP is a common second messengerproduced in response to hormones and other chemical signals. It is formed from ATP in a reactioncatalyzed by adenylate cyclase.356Part II Structure and CatalysisFurther ReadingGeneralFriedberg, E.C. (1985) DNA Repair, W.H. Freeman and Company, New York.A good source for more information on the chemistry of nucleotides and nucleic acids.Kornberg, A. & Baker, T.A.
(1991) DNA Replication, 2nd edn, W.H. Freeman and Company, NewYork.The best place to start for learning more about DNAstructure.Saenger, W. (1984) Principles of Nucleic AcidStructure, Springer-Verlag, New York.A more detailed treatment.Watson, J.D., Hopkins, N.H., Roberts, J.W.,Steitz, J.A., & Weiner, A.M. (1987) Molecular Biology of the Gene, 4th edn, The Benjamin/Cummings Publishing Company, Menlo Park, CA.Excellent general reference.Variations in DNA StructureDickerson, R.E. (1983) The DNA helix and how itis read. Sci. Am. 249 (December), 94-111.Htun, H. & Dahlberg, J.E. (1989) Topology andformation of triple-stranded H-DNA. Science 243,1571-1576.Rich, A., Nordheim, A., & Wang, A.H.-J.
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