Cytidine triphosphate structure

It was snbseqnently discovered that the first enzyme in the pathway for isoleucine synthesis, which is threonine deaminase, was inhibited by isoleucine in an extract of E. coli. No other amino acid caused inhibition of the enzyme. Threonine deaminase is, in fact, the rate-limiting enzyme in the pathway for isoleucine synthesis, so that this was interpreted as a feedback control mechanism (Fignre 3.13(a)). Similarly it was shown that the hrst enzyme in the pathway for cytidine triphosphate synthesis, which is aspartate transcarbamoylase, was inhibited by cytidine triphosphate (Fignre 3.13(b)). Since the chemical structures of isoleucine and threonine, or cytidine triphosphate and aspartate, are completely different, the qnestion arose, how does isolencine or cytidine triphosphate inhibit its respective enzyme The answer was provided in 1963, by Monod, Changenx Jacob. 

Molecules with structures as diverse as carbamoyl-phosphate, tryptophan, and cytidine triphosphate are feedback inhibitors of the E. coli glutamine synthase. The feedback inhibition is cumulative, with each metabolite exerting a partial inhibition on the enzyme. Why would complete inhibition of the glutamine synthase by a single metabolite be metaboli-cally unsound ... 

Figure 10.2. CTP luhibits ATCase. Cytidine triphosphate, an end product of the pyrimidine synthesis pathway, inhibits aspartate transcarbamoylase despite having little structural similarity to reactants or products.

I. L. Monoco, J. L. Crawford, and W. N. Lipscomb Three dimensional structures of aspartate transcarbamoylase from Escherichia coli and its complex with cytidine triphosphate. Proceedings of the National Academy of Sciences USA. 75,5276 (1978). 

Perhaps the best-studied regulatory enzyme of this kind is aspartate transcarbamoy-lase (ATCase), which catalyzes the first steps in the biosynthetic pathway leading to uridine and cytidine nucleotides. Today, a great amount of information, structural, thermodynamical, and kinetic, is available on this system. Specifically it is known that cytidine triphosphate (CTP) inhibits ATCase. (Other molecules, such as ATP, activate the same enzyme. We shall focus, in this section, on inhibitory effectors only.)... 

From this point, MEP is coupled to cytidine triphosphate to produce 4-diphosphocytidyl-2C-methyl-D-erythritol (CDP-ME) in a reaction, which is catalyzed by 4-diphospho-cytidyl-2C-methyl-D-erythritol transferase (IspD) [2.7.7.60] (Scheme 5.2). IspD structure-mechanism analysis showed that a sequential mechanism applies with a Mg ion coordinating first, followed by CTP binding and then MEP [22]. The cytosine base portion of the substrate or the product is hydrogen bonded to Ala 14, Alai 5, Gly82, Asp 83, and Sep88 based on smdies conducted on product-bound cocrystal of IspD from E. coli [23]. 

Using cytidine mono-, di-, and triphosphate as an example, the mean excitation energies are found fo be 74.00, 76.96, and 79.22 eV, respectively. The variation in the other nucleotides with phosphate number is expected to parallel this behavior. Again, variation of fhe defails of the biomolecule structure makes little difference. 

Cytidine phosphates cytidine S -monophosphate (CMP, cytidylic acid, M, 323.2), cytidine 5 -diphos-phate (CDP, M, 403.19) and cytidine 5 -triphosphate (CTP, M, 483.16). For structure, see e. g. Pyrimidine biosynthesis. CTP is a precursor of RNA synthesis, while deoxy-CTP is a precursor of DNA synthesis. CDP may be regarded as the coenzyme of phospholipid biosynthesis (see Membrane lipids) (activated choline is CDP-choline). Glycerol and the sugar alcohol, ribitol, are also activated by bonding to CDP (see Nucleoside diphosphate sugars). Reduction of ribose... 

The nucleotide coenzymes are structurally related to the mononucleotides. Typical nucleotide coenzymes are adenosine triphosphate (ATP), flavin-adenine-dinucleotide (FAD) and numerous other phosphate esters of complex structure, containing adenosine, guanosine, cytidine or uridine. Five coenzymes are known for example, which are derived from cytidine diphosphate (CDP) CDP-choline, CDP-ethanolamine, CDP-diglyceride, CDP-glycerol and CDP-ribitol. 

Figure 10 Chemical structures of adenosine 5 -monophosphate (n = 1 AMP ), adenosine 5 -diphosphate (n = 2 ADP "), and adenosine 5 -triphosphate (n = 3 ATP ) as well as of cytidine 5 -monophosphate (n = 1 CMP, cytidine 5 -diphosphate (n = 2 CDP ), and cytidine 5 -triphosphate (n = 3 CTP ) in their dominating anti conformation [11-14,50]. Note, the triphosphate chain in nucleoside 5 -triphosphates (NTP ) is labeled a, P, and y, where y refers to the terminal phosphate group (see also Figure 9) for nucleoside 5 -diphosphates (NDP ) the situation is analogous with a and P (see Figure 9). The adenine and cytosine residues in the nucleotide structures shown above may be replaced by one of the other nucleobase residues shown in Figiue 1 if this substitution is done in the way the bases are depicted within the plane (Figure 1), then the anti conformation will also result for the corresponding nucleoside 5 -phosphates. The abbreviations AMP, ADP , ATP , IMP, etc. in this text always represent the 5 -derivatives 2 - and 3 -derivatives are defined by 2 AMP, 3 AMP, etc. in a few instances where uncertainties might otherwise occur, the abbreviations 5 AMP , 5 ADP , etc. are also used.

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