Urea cycle

Urea synthasis disorders in molecular level


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1. UREA CYCLE DISORDERS Nandini H.S. Prabhudas MAHE Usha S . MADHURI 2 nd M.Sc. SDUAHER

2. Outline of the presentation Introduction Disorders of urea cycle Types Molecular basis Clinical aspects Summary

3. Introduction The urea cycle is a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is removed from the blood and converted to a compound called urea Urea is the major end product of protein metabolism Deficiency of the enzymes that are involved in the urea cycle leads to various disorders or urea cycle disorders Urea cycle disorders are characterized by hyperammonemia which is excess accumulation of ammonia in blood Continuation…….

4. Urea is the major excretory product in humans, accounting for an average of 86% of nitrogen is eliminated Urea is synthesized in liver and transported to kidneys for excretion in urine Urea synthesis is a five step cyclic process with five distinct enzymes The first two enzymes are present in mitochondria while the rest are localized in cytosol

5. Schematic representation of urea cycle

6. No. Disorder Gene Enzyme deficiency Inheritance pattern 1. Carbamoyl phosphate synthetase deficiency CPS1 Carbamyl phosphate synthetase Autosomal recessive 2. Ornithine transcarbamylase defeciency OTC Ornithine transcarbamylase X - linked 3. Citrullinemia ASS1 and SLC25A13 Arginosuccinate synthetase Autosomal recessive 4. Argininosuccinic aciduria ASL Arginosuccinate lyase Autosomal recessive 5. Argininemia ARG1 Arginase Autosomal recessive Urea Cycle Disorders

7. 1) Carbamoyl phosphate synthetase defeciency Carbamoyl phosphate synthetase deficiency is an inherited disorder that causes hyperammonemia due to carbamoyl phosphate synthetase enzyme deficiency Inheritance pattern - Autosomal recessive(which means both copies of the gene in each cell have mutations)

8. Molecular basis Mutations in the CPS1 gene cause carbamoyl phosphate synthetase deficiency CPS1 gene codes carbamoyl phosphate synthetase enzyme The role of this enzyme is to catalyze the first step in the urea cycle as it converts ammonia and carbon dioxide into carbamoyl phosphate in the presence of ATP Deficiency of this enzyme leads to nitrogen accumulation in the blood stream Nitrogen accumulates in the form of toxic ammonia instead of being converted to less toxic urea and excreted

9. 2) Ornithine transcarbamylase (OTC) defeciency Ornithine transcarbamylase deficiency causes ammonia to accumulate in the blood due to defective ornithine transcarbamylase enzyme Inheritance Pattern : X – linked

10. Mutations in the OTC gene cause ornithine transcarbamylase deficiency OTC gene codes ornithine transcarbamylase enzyme It is responsible for converting carbamoyl phosphate and ornithine into citrulline Defeciency of this enzyme leads to nitrogen accumulation in the bloodstream in the form of ammonia Molecular basis

11. 3) Citrullinemia Citrullinemia is chracterized by hyperammonemia due to deficiency of arginosuccinate synthetase enzyme Types type I  citrullinemia  develops in childhood type II  citrullinemia  is adult onset Inheritance pattern - Autosomal recessive

12. Molecular basis Mutations in the ASS1 and SLC25A13 genes are responsible for citrullinemia Mutations in the ASS1 gene cause type I citrullinemia ASS1 gene codes argino succinate synthase 1 this is responsible for one step of the urea cycle Mutations in the ASS1 gene results in the enzyme deficiency which disrupts the urea cycle and prevents the body from processing nitrogen effectively Excess nitrogen (in the form of ammonia) and other by products of the urea cycle accumulate in the bloodstream

13. SLC25A13 gene Mutations in the SLC25A13 gene are responsible for adult-onset type II citrullinemia This gene codes for a protein called citrin Citrin helps in the transportation of molecules used in the production and breakdown of simple sugars, proteins in the urea cycle Mutations in the SLC25A13 gene, leads to deficiency of citrin , which inhibits the urea cycle The resulting buildup of ammonia and other toxic substances leads to the signs and symptoms of adult-onset type II citrullinemia

14. 4) Argininosuccinic aciduria Argininosuccinic aciduria , also called  argininosuccinic acidemia , is an inherited disorder that causes the accumulation of argininosuccinic acid (ASA) in the blood and urine Inheritance Pattern : Autosomal recessive

15. Molecular basis Mutations in the ASL gene cause argininosuccinic aciduria ASL gene codes arginosuccinate lyase enzyme which catalyze the conversion of arginosuccinic acid into arginine in urea cycle Mutations ASL gene leads to arginosuccinate lyase enzyme deficiency Enzyme defecient in the cycle leads to arginosuccinic aciduria condition and nitrogen accumulates in the blood and urine in the form of ammonia

16. 5) Argininemia Argininemia is characterized by accumulation of amino acid arginine and ammonia in the blood due to arginase defeciency Inheritance Pattern – Autosomal recessive

17. Molecular basis Mutations in the ARG1 gene causes argininemia The ARG1 gene codes for an enzyme called arginase This enzyme catalyzes the final step of the urea cycle, which produces urea by removing nitrogen from arginine Mutations in ARG1 gene results in the deficiency of arginase as a result, urea cannot be produced normally and excess nitrogen accumulates in the blood in the form of ammonia

18. Common clinical features Hyperammonemia causes neurological problems like seizures developmental delay intellectual disability memory loss and abnormal behaviors This also leads to progressive liver damage Management Dietary protein restriction is considered a mainstay of the long-term management of hyperammonemia

19. Summary Carbamoyl phosphate synthetase deficiency - Carbamoyl phosphate synthetase Ornithine transcarbamylase defeciency - Ornithine transcarbamylase Citrullinemia - Arginosuccinate synthetase Argininosuccinic aciduria - Arginosuccinate lyase Argininemia - Arginase .