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Looking at the conventional structure formula of ATP, one’s first impression is that of great complexity. Nature does not indulge in luxuries, so one may wonder why the cell uses such a complex molecule if a P—O—P link is all that is needed. A much simpler inorganic polyphosphate should do just as well.
In contrast to fats, carbohydrates, and proteins, the pyrimidine and purine nucleotides do not contribute significantly as fuels for energy metabolism in humans. They are essential to life for other reasons. Although it is true that some nucleotides do play essential roles in metabolism as structural components of the co-catalytic partners of enzymes, their major function is to participate in the processes of reproduction and growth. The nucleotides serve as the structural components of the macromolecules which store, replicate, transcribe, and translate the genetic information.
The pathways of biosynthesis of the four major ribonucleotides and the four deoxyribonucleotides are well established and are now described in every elementary text. As a review, these reactions are summarized below.
Term Paper # 1. Synthesis of Purine Nucleotides:
The metabolites serving as precursors of the purine ring system are as follows:
De novo synthesis of the purine nucleotides begins not with the ring system itself but rather with an activated form of D- ribose-5 –phosphate –
The numbering in the intermediates shown below correspond to the atom numbers of the finished purine ring. In a reaction with glutamine, the entire pyrophosphate group is displaced by the amide N and at the same time the configuration of the number one carbon atom is inverted to the β-form –
Starting with this N, the ring system synthesis continues by the formation of an amide linkage with the carboxyl group of glycine.
A one-carbon unit, or active formate, is now added to the amino N of the glycine moiety.
The donor of this C atom is N5, N10-methenyltetrahydrofolate (in the reactions below, the 5-phospho-β-D-ribosyl moiety will be abbreviated as R and tetrahydrofolate as FH4) –
Before the five-membered ring of the purine system is closed, the N that will be number 3 is introduced by glutamine in an ATP and Mg2+ dependent reaction. The amide N is transferred to C-4.
The imidazole ring system is now formed by the elimination of water between C-8 and N-9 in an ATP-driven and Mg2+ – K+– dependent reaction –
C-5 of the imidazole ring is next carboxylated to give what will become C-6 of the finished purine ring system –
N10-Formyltetrahydrofolate contributes the remaining carbon (number 2) for the purine ring –
With the elimination of HOH, purine synthesis is completed and the product of the process is inosine monophosphate (IMP) –
It may be useful at this juncture to be reminded of the energy needed for the synthesis of the purine ring system. In the first step of the biosynthetic sequence (the formation of PRPP) ATP transfers a pyrophosphate moiety and the energy expenditure of this step is thus equivalent to that of two high-energy phosphates. Each of four of the subsequent reactions require an ATP, giving a total of six high-energy phosphates utilized for the synthesis of inosinic acid.
Formation of Adenylic Acid and Guanylic Acid from Inosinic Acid:
In order to replace the oxo group at C-6 of inosinic acid with an amino group to yield adenylic acid, a complex, GTP-dependent reaction with aspartate is required –
As in other reactions in which aspartate serves as an NH2 donor, this intermediate is split to give fumarate. The other product is adenylic acid –
Accounting for the hydrolysis of the GTP to GDP and P, the de novo synthesis of adenylic acid requires a total energy expenditure of seven high-energy phosphates. The synthesis of the second major purine nucleotide, guanylic acid, begins with the dehydrogenation of inosinic acid –
An amino group is substituted on C-2 by glutamine, a process that requires the cleavage of ATP to AMP and PP –
From the foregoing reactions, it can be seen that eight high- energy phosphates are expended in the total synthesis of guanylic acid.
Catalyzed by kinases, AMP and GMP can be converted to the triphosphate forms:
Term Paper # 2. Synthesis of the Pyrimidine Nucleotides:
It will be recalled that the first step in urea synthesis is a mitochondrial reaction between NH4+, HCO3–, and ATP, yielding carbamoyl phosphate. Pyrimidine biosynthesis also begins with the formation of carbamoyl phosphate. However, in contrast to the urea synthesis system, the carbonyl phosphate that is a precursor of the pyrimidine ring is produced in the cytosol from glutamine –
In the next reaction aspartate accepts the carbamoyl moiety with a loss of the phosphate –
With the elimination of HOH, the ring is closed and the product is dihydroorotate –
In an NAD+-dependent dehydrogenation, mediated by a flavoprotein containing FAD, FMN, and iron-sulfur centers, the dihydroorotate is converted to orotate –
In a sequence of two reactions, perhaps catalyzed by the same enzyme system, the orotate accepts a ribosyl phosphate from PRPP and is also decarboxylated to yield uridylic acid –
By successive phosphorylations by ATP, catalyzed by specific kinases, the uridylic acid is converted to UTP.
Formation of Cytidine Triphosphate:
In eukaryotic cells the four carboxo portions of UTP can be aminated with glutamine in an ATP-dependent reaction to yield cytidine triphosphate (CTP) –
Term Paper # 3. Deoxyribonucleotides:
In the deoxyribonucleotides that are the building blocks of DNA, C-2 of the ribose has two hydrogens –
The reduction of C-2 occurs only when the ribose is in its nucleotide form. Specifically, it is the purine and pyrimidine nucleoside diphosphates (ADP, GDP, UDP, and CDP) that are reduced to the deoxy analogs- dADP, dGDP, dUDP, and dCDP. The reductant of the ribotides is a protein dithiol (thioredoxin) –
The oxidized thioredoxin is returned to its dithiol state by reduction with NADPH + H+, catalyzed by a flavo (FAD) protein. The overall process can be summarized as follows –
Synthesis of Deoxythymidylic Acid:
Deoxythymidylic acid (5-methyl-dUMP), one of the pyrimidine nucleotides of DNA, is formed from deoxyuridylic acid by a unique reaction with N5, N10-methylenetetrahydrofolate. Since the methylene moiety is at the oxidation level of formaldehyde, additional electrons must be provided for the one carbon unit to be reduced to the methyl group of thymine.
The source of these electrons is the tetrahydrofolate itself and, accordingly, the overall stoichiometry of thymidylate synthesis can be formulated as follows –
The dihydrofolate is restored to its tetrahydro form by reduction with NADPH and H+:
Degradation and Reutilization of Purines:
Both the nucleic acids ingested in our food and those synthesized endogenously are subject to enzymatic hydrolysis by nucleases. The attacks on the 3′ and 5′ sides of the phosphodiester bridges are specific and also recognize the nitrogenous bases, in the nucleotides as illustrated by the following examples.
An endonuclease of pancreas attacks 3′ linkages of DNA to yield quartets of nucleotide residues another endonuclease of the spleen and thymus catalyzes hydrolysis of 5′ bridges; a pancreatic ribonuclease, specific for 5′ linkages in which the 3′ bridge is to a pyrimidine nucleotide, yields pyrimidine 3′-phosphaies and oligonucleotides whose terminuses are pyrimidine 3′-phosphates. Degradation to the free purines and pyrimidine is completed by the action of phosphatases and hydrolases.
The end product of the purines in humans is uric acid:
In an adult only about 10 percent of the free purines formed as catabolic products is excreted as uric acid. The remainder of the purines can be salvaged for nucleotide synthesis.
Adenine, guanine, and hypoxanthine are recycled to their nucleotide forms by reactions with PRPP:
Adenine + PRPP → AMP + PP
Guanine + PRPP → GMP + PP
Hypoxanthine + PRPP → IMP + PP
Alternatively, the purines can undergo a phosphorylase-type reaction with ribose-1-phosphate:
Adenine or guanine + ribose-1-phosphate → AMP or GMP + Pi
Formation of Urea and Ammonia from Pyrimidines:
The uracil produced from the deamination of cytosine can be reduced by an NADH-dependent reaction to give dihydrouracil –
By hydrolytic cleavage, this compound is converted to b-alanine, NH4+ and HCO3–.