Content Reviewers:Elizabeth Nixon-Shapiro, MSMI, CMI, Marisa Pedron, Viviana Popa, MD, Rishi Desai, MD, MPH
Nucleotides are the building blocks of nucleic acids - deoxyribonucleic acid, or DNA - and ribonucleic acid, or RNA. The most basic structure of the nucleotide can be broken down into three subunits - a five carbon sugar, a phosphate group, and a nitrogenous base, also known as nucleobase.
So, the five carbon sugar is either deoxyribose or ribose - and depending on which is used, the final product is either deoxyribonucleic acid, or ribonucleic acid. The nucleobases can be either pyrimidines or purines. There are 3 pyrimidine bases, and they are all made up of a single heterocyclic ring - cytosine, or C, thymine, or T - which is DNA-specific, or T, and uracil, or U, which is RNA-specific. There are two purine bases, adenine, or A, and guanine, or G, and they’re made up of two rings. Now if we link up just the sugar and the nucleobase, we’ve got ourselves a nucleoside. To make a nucleotide, all we’ve got to do is add a phosphate group to the 5th carbon of the sugar on a nucleoside.
So, nucleosides have slightly different names - in RNA, ribose plus adenine makes adenosine, guanine makes guanosine, cytosine makes cytidine, and uracil makes uridine. So, adding a phosphate, the “full name” of RNA nucleotides would actually be adenosine monophosphate, or AMP, guanosine monophosphate, or GMP, cytidine monophosphate, or CMP and uridine monophosphate - or UMP. For DNA, we’re using deoxyribose instead of ribose, so the nucleosides would be deoxyadenosine, deoxyguanosine, deoxycytidine and deoxythymidine - and similarly, with addition of phosphate group, the nucleotide would be called, for example, deoxyguanosine monophosphate, or dGMP. We know, all of this sounds complicated. Don’t shoot the messenger.
There are two ways our cells can make nucleotides - one is to make from scratch, also known as de novo synthesis, and the other is the salvage pathway, that recycles nucleotides that are already semi-degraded. Let’s begin with the ribose-containing nucleotide synthesis.
De novo synthesis starts with ribose-5-phosphate for both purine and pyrimidine bases. Ribose-5-phosphate comes from another intracellular metabolic pathway called the pentose phosphate pathway. And an enzyme called ribose phosphate pyrophosphokinase uses an adenosine triphosphate - or ATP - molecule, and removes two phosphate groups from it, attaching them to to ribose-5-phosphate, creating a phosphoribosyl pyrophosphate - or PRPP. We’ll need this later on.
Next step is to make pyrimidines. We’ll need the amino acid glutamine, some bicarbonate, water, and ATP. An enzyme called carbamoyl phosphate synthetase II will then create carbamoyl phosphate which is joined to aspartate by the enzyme aspartate transcarbamoylase - or ATCase, for short. Together, they form a ringed molecule called carbamoyl aspartic acid, which gets dehydrated by dihydroorotase to create a molecule called orotate. Next, the enzyme orotate phosphoribosyltransferase moves the phosphoribose unit from PRPP to orotate and that forms orotidine monophosphate, or OMP. After this, the enzyme UMP synthase converts orotidine monophosphate into uridine monophosphate, or UMP. That UMP gets phosphorylated twice by nucleoside diphosphate kinase, to become uridine triphosphate, or UTP. Finally, the enzyme CTP synthase, converts uridine triphosphate into cytidine triphosphate, or CTP. And before CTP is used as a nucleic acid, it serves as an energy source in other cellular reactions and thereby loses two phosphates.