Nucleotide metabolism

Definitions & Key takeaways

Nucleotide metabolism refers to the metabolic processes that involve the synthesis and breakdown of nucleotides. A nucleotide is a building block of DNA or RNA. Each nucleotide consists of a nitrogenous base, a sugar, and a phosphate group. Nitrogenous bases are divided into purines, which are adenine and guanine; and pyrimidines, which include cytosine, thymine, and uracil. The sequence of nitrogenous bases in DNA and RNA determines the identity of the genetic information found in living organisms.

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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.
Purine synthesis is a bit more complex. It starts with the amino acids glutamine, aspartate, and glycine, together with carbon dioxide and a special form of tetrahydrofolate, or THF, called 10-formyl-THF.
These undergo a ten-step pathway with the help of a number of enzymes, with names that will assure you a victory in Hangman.
The result of all this is inosine monophosphate, or IMP, which is sort of a generic purine. IMP is converted to AMP in two steps.
First, an enzyme called adenylosuccinate synthase uses energy from a GTP molecule to add aspartate to IMP, forming adenylosuccinate.
Then, another enzyme called adenylosuccinate lyase cleaves adenylosuccinate into AMP and a fumarate molecule. Alternatively, IMP can become GMP.
To do that, IMP gets oxidized by IMP dehydrogenase to become xanthosine monophosphate, or XMP. Then, an enzyme called GMP synthase transfers an amino group from glutamine to xanthosine monophosphate, making GMP.Okay, so now that we have RNA nucleotides, making DNA ones is relatively straightforward.
RNA nucleotides are usually in the monophosphate form. For the metamorphosis from RNA to DNA molecules to happen, we need them in diphosphate form, so CDP, UDP, ADP, and GDP.
Next, an enzyme called ribonucleotide diphosphate reductase will reduce the ribose within them into deoxyribose, creating dCDP, dUDP dADP, and dGDP.
After this, they just need to lose a phosphate group, and we’ll have dCMP, dUMP, dAMP, and dGMP. But, something is missing - dTMP.
Making this is also fairly simple. dUMP gets converted by thymidylate synthase into dTMP, and at that point we’re all set to make DNA.Now, pyrimidine rings - C, T and U - can be degraded completely back down to carbon dioxide -CO2 - and ammonia - NH3, which can then be excreted through exhalation from the lungs and into urine.
In contrast, purine rings, or G and A - cannot be broken down in quite the same way. Instead, they’re degraded down to the metabolically inert uric acid which is then excreted into urine.
For GMP to become uric acid, the enzyme purine nucleoside phosphorylase, first removes the ribose and the phosphate from it, turning it into guanine.
Next, another enzyme called guanase removes an amine group turning guanine into xanthine. Finally, xanthine is oxidized into uric acid by the enzyme xanthine oxidase.
On the other hand, for AMP to become uric acid, first the enzyme AMP deaminase removes an amine group from it, turning it into IMP.
Then purine nucleoside phosphorylase comes in and removes the phosphate and the ribose from IMP, making hypoxanthine. Hypoxanthine is then oxidised twice by xanthine oxidase - first to become xanthine, and then finally, to uric acid.
While uric acid is metabolically inert, an issue may arise if it builds up in the body - which can happen either because of excess production, or slow removal.
When there’s too much uric acid, it gets into tissues, like joints or tendons, and can become monosodium urate, which is a salt - and salts like to crystallize.
So crystals start forming in the tissues, and in response the body starts to secrete proteins around them - and the protein covered crystals are called tophi.
These tophi cause an inflammatory reaction called gout - which most often involves the joint in the big toe.Now, it turns out that those intermediate molecules in purine degradation, guanine and hypoxanthine, can be restored into fresh new nucleic acids, through what is known as a salvage pathway The enzyme hypoxanthine- guanine phosphoribosyl transferase, or HGPRT for short, returns ribose and phosphate back to guanine to form GMP, and to hypoxanthine to form IMP.
From there, IMP can become AMP again, following the AMP synthesis pathway from before. A genetic disease, called Lesch-Nyhan syndrome is characterized by a complete absence of HGRPT.
And as a result, there’s too much uric acid getting produced by purine degradation. Since the uric acid can’t get recycled, and our excretion is kinda slow to begin with, it begins getting stored up in tissues, causing gout.
Lesch-Nyhan causes a number of symptoms like self-mutilation, and one distinctive one is that it causes symptoms of gout in very young patients, which is highly unusual - so another name for it is juvenile gout.
Alright, as a quick recap. The nucleotide is a building block of DNA or RNA, and it’s made out of three parts - the phosphate group, five carbon sugar, and a nucleobase.
The nucleobases are divided into purines, adenine and guanine; and pyrimidines, cytosine, thymine, and uracil. They are produced within the cytosol, either through salvage pathways, or created anew through their respective pathways - for pyrimidines, we need amino acid glutamine, aspartate, some bicarbonate, water, and ATP, and for purines, we need amino acids glutamine, aspartate, and glycine, together with carbon dioxide and a special