pyrimidine metabolism

hello everyone, this DeepInMed blog hope you all doin well. 

So today we are going to talk about pyrimidine metabolism last lesson in the molecular biology chapter, congrats you just made the first step. 

well then pyrimidine synthesis may be similar to purine synthesis since both of them are nucleotides they share sources of atoms which are glutamine, aspartic acid and CO2. 

this the whole process shown in the figure 

the first step is synthesis of carbamoylphosphate from glutamine and the enzyme that catalyze this step is carbamolyphosphate synthetase II (CPS II) in case you were wondering there is carbamoylphosphate I (CPS I)which found in the mitochondria and it's important for urea cycle while our enzyme here works on pyrimidine synthesis here is more details about them 

most important thing to know that is step is rate limiting step for this pathway and carbamoylphosphate synthetase II is inhibited by UMP 

The second step in pyrimidine synthesis is the formation of carbamoylaspartate,

catalyzed by aspartate transcarbamoylase. The

pyrimidine ring is then closed hydrolytically by dihydroorotase. The

resulting dihydroorotate is oxidized to produce orotic acid or orotate and the enzyme that produce it is dihydroorotate dehydrogenase here is a thing you may want to know that is enzyme is the only enzyme in pyrimidine synthesis which is embeded in the inner mitochondrial membrane when all the other enzymes are cytosolic. 

now after we have the orotic acid it's time to make OMP stands for ortidine 5 monophosphate PRPP is again the ribose

5-phosphate donor. The enzyme orotate phosphoribosyltransferase

produces OMP and releases pyrophosphate. OMP, the parent pyrimidine mononucleotide,

is converted to uridine monophosphate (UMP) by orotidylate decarboxylase,

which removes the acidic carboxyl group. 

the other pyrimidines are been synthsized from UMP itself. here is the most high yield things to know about pyrimdine synthesis : 

glutamine → carbamoylphosphate → orotic acid  →  UMP 

diseases that related to this process 

orotic aciduria : this an acutosomal recessive disorder where children born with it defect in UMP synthetase which apparently leads to cut out this process and accumulation of orotic acids and here where is the reason we get the name of orotic aciduria. symptoms orotic acid appear in urine for sure, megaloblastic anemiea (and the reason most patients develop it because B 12 or folate deficincy) and growth retardation. treatment : just give them uridine directly. 

there is another disorder cause accumulation of orotic acids in the urine which is orinthine transcarbamylase deficincy (OTC) which is important enzyme in the urea cycle it combines carbamoylphosphate with orinithine to give citrulline. and when you don't have this enzyme carbamoylphosphate will have no other way but to back to pyrimidine synthesis pathway which will make more orotic acid than the body needs and patients will have the same symptoms of orotic aciduria but don't be confused there is a way to distinguish between them since ONLY in OTC patients will have high levels of ammonia because the urea cycle is dysfuntion while in orotic aciduria it's intact and the baby born with this disorder will have encephalopathy ( lethargy and coma) because of dysfunction urea cycle. 

now back to the pyrimidine synthesis pathway, after we have UMP it convert to UTP by adding to more phosphate from ATP and then converted to CTP and the requries removal of an oxygen group and addition of nitrogen group as shown in the figure below 

there is a chemotherapy agent the mimics the structure of cytidine it called Ara - c (cytarabinose cytosine arabinoside) once it is inside the body it converted to areCTP which mimics dCTP and inhibit DNA polymerase.

now with been said lets move to thymdine synthesis and since this one is only used in DNA that means it only required as nucleotide as deoxythymdine and it is synthesis from dUTP just by adding one carbon molecule and this process consist of three steps 

thymdien synthesis :

step one : UMP → dUDP  enzyme catalyze this step is ribonucleotide reductase 

drugs related to this step : hydroxyurea 

this one inhibit ribonucleotide reductase so it will certainly block formation of deoxyribonucleotides but RNA stay intact, rarely used for malignancy and most common use for polycythemia vera and thrombocytosis, use in sickle cell anemia and causes increase fetal hemoglobin levels (mechanism unknow yet)

step 2 : dUDP  →  dUMP 

step 3 : dUMP  →  dTMP 

and this step is catalyzed by thymidlate synthase.