Pyrimidine Synthesis - CRASH! Medical Review Series 

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On regards to Pyrimidine Synthesis, the following are the steps: 1) The Synthesis begins with 2 ATP Molecules, Carbon Dioxide (CO2), and Glutamate Amino Acid Reactants via Carbamoyl Phosphate Synthase II (CPS II) to; 2) Carbamoyl Phosphate to; 3) Dihydroorotate to 4) Orotate (Orotic Acid) via reaction with Dihydroorotate Dehydrogenase (DHODH) to; Uridine Monophosphate (UMP) to Uridine Triphosphate (UTP) to Cytidine Triphosphate (CTP) via Cytidine Triphosphate Synthetase catalysis (Rate Limiting Enzyme). Also, in De Novo Pyrimidine Synthesis Deoxyuridine Monophosphate (dUMP) to Deoxythymidine Monophosphate (dTMP) via Thymidylate Synthetase (Synthase). In Regards of Pharmacology relevant herein, the Immunomodulatory Agents Teriflunomide and Leflunomide (Substrate Precursor of the Latter) inhibits the catalytic Enzyme of DHODH. These Medications can Treat Autoimmune Diseases of Rheumatoid Arthritis (RA), Psoriatic Arthritis (PA) and Multiple Sclerosis (MS or Relapsing Type). Methotrexate (MTX, Amethopterin) is an Antimetabolite Drug Class or a Folic Acid Analog with Mechanism of Action (MOA) of Inhibition of Dihydrofolate Reductase (DHFR) indirectly inhibiting Thymidylate Synthase. Also, 5-Fluorouracil (5 FU) is a Pyrimidine Analog Drug Class which is converted metabolically to its toxic form, Fluorodeoxyuridylate (F-dUMP) and thereby Inhbiting DNA Synthesis and Arresting the Cell Cycle at the Synthesis Phase (S Phase Cell Cycle Arrest) and is commonly used as an Immunosuppressant just as a Antineoplastic Agent in Chemotherapy. Congenital Pathology in this Pathway includes Orotic Aciduria (DDx: Cobalamine/Folate Deficiency Megaloblastic Anemia; Dx: Elevated Orotic Acid in Urine Assay) where UMPS is Deficient if not Totally Absent. In Severe Combined Immunodeficiency (SCID) Enzyme Deficiency is ADA (rather ADA SCID) where Adenosine buildup and thereby dATP which inhibits Ribonucleotide Reductase (RNR) impeding Conversion of Ribonucleotides to Deoxyribonucleotides (DNA Synthesis Inhibition causing Panleukopenia in a Neonate; Dx: Neonatal Screening). It is useful to understand Carbamoyl Phosphate Synthase I (CPS I) is involved in a different reaction for a wholly different Pathway, namely Urea Cycle where Ammonia (NH3) is the Reactant. Goodness, I have just delivered an ultra rare disease of a Neonate which is the first to respond to CRISPR-CAS 9 Gene Therapy. The Technieque to incise the ADA Gene and replace it with a functional Gene. Just kidding, the Neonate has Thymic Alymphoplasia SCID. MD Paul Bolin, es geht sehr gut zu sehen und denken aber nicht arbeiten....Prost!

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