Synthesis of nucleic acids
Nucleotides can be separated into purines and pyrimidines. They are both primarily produced in the liver. They both contain a sugar and a phosphate, but have nitrogenous bases that are different sizes. Because of this, the two different groups are synthesized in different ways. However, all nucleotide synthesis requires the use of phosphoribosyl pyrophosphate (PRPP) which donates the ribose and phosphate necessary to create a nucleotide.
The origin of atoms that make up purine bases.
Adenine and guanine are the two nucleotides classified as purines. In purine synthesis, PRPP is turned into inosine monophosphate, or IMP. Production of IMP from PRPP requires glutamine, glycine, aspartate, and 6 ATP, among other things. IMP is then converted to AMP (adenosine monophosphate) using GTP and aspartate, which is converted into fumarate. While IMP can be directly converted to AMP, synthesis of GMP (guanosine monophosphate) requires an intermediate step, in which NAD+ is used to form the intermediate xanthosine monophosphate, or XMP. XMP is then converted into GMP by using the hydrolysis of 1 ATP and the conversion of glutamine to glutamate. AMP and GMP can then be converted into ATP and GTP, respectively, by kinases that add additional phosphates.
ATP stimulates production of GTP, while GTP stimulates production of ATP. This cross regulation keeps the relative amounts of ATP and GTP the same. Excess of either nucleotide could increase the likelihood of DNA mutations, where the wrong purine nucleotide is inserted.
Lesch-Nyhan syndrome is caused by a deficiency in hypoxanthine-guanine phosphoribosyltransferase or HGPRT, the enzyme that catalyzes the reversible reaction of producing guanine from GMP. This is a sex-linked congenital defect that causes overproduction of uric acid along with mental retardation, spasticity, and an urge to self-mutilate.
Uridine-triphosphate (UTP), at left, reacts with glutamine and other chemicals to form cytidine-triphosphate (CTP), on the right.
Pyrimidine nucleotides include cytidine, uridine, and thymidine. The synthesis of any pyrimidine nucleotide begins with the formation of uridine. This reaction requires aspartate, glutamine, bicarbonate, and 2 ATP molecules (to provide energy), as well as PRPP which provides the ribose-monophosphate. Unlike in purine synthesis, the sugar/phosphate group from PRPP is not added to the nitrogenous base until towards the end of the process. After uridine-monophosphate is synthesized, it can react with 2 ATP to form uridine-triphosphate or UTP. UTP can be converted to CTP (cytidine-triphosphate) in a reaction catalyzed by CTP synthetase. Thymidine synthesis first requires reduction of the uridine to deoxyuridine (see next section), before the base can be methylated to produce thymidine.
ATP, a purine nucleotide, is an activator of pyrimidine synthesis, while CTP, a pyrimidine nucleotide, is an inhibitor of pyrimidine synthesis. This regulation helps to keep the purine/pyrimidine amounts similar, which is beneficial because equal amounts of purines and pyrimidines are required for DNA synthesis.
Deficiencies of enzymes involved in pyrimidine synthesis can lead to the genetic disease Orotic aciduria which causes excessive excretion of orotic acid in the urine.
Converting nucleotides to deoxynucleotides
Nucleotides are initially made with ribose as the sugar component, which is a feature of RNA. DNA, however, requires deoxyribose, which is missing the 2'-hydroxyl (-OH group) on the ribose. The reaction to remove this -OH is catalyzed by ribonucleotide reductase. This enzyme converts NDPs (nucleoside-diphosphate) to dNDPs (deoxynucleoside-diphosphate). The nucleotides must be in the diphosphate form for the reaction to occur.
In order to synthesize thymidine, a component of DNA which only exists in the deoxy form, uridine is converted to deoxyuridine (by ribonucleotide reductase), and then is methylated by thymidylate synthase to create thymidine.