what is krebs cycle

 krebs cycle

the integration of urea cycle to krebs (tricarboxylic acid ;TCA )cycle is known as krebs bicycle hans krebs was involved in the diversity of both these cycles.it is also known as the aspartate - argininosuccinate shunt fumarate producing in the urea cycle is an integrating point to the krebs cycle in hepatic cytosol, fumarate is converted sequentially to malate dehydrogenase respectively. malate is either transported via the malate aspartate shuttle or oxaloacetate (a keto acid).finally a transamination reaction in the mitochondria between oxaloacetate and glutamate forms aspartate which is transported to cytosol to be used again as nitrogen donor in the urea cycle.

these reaction together constitute aspartate -argininosuccinate shunt the shunt provided metabolic links between separate pathways by which the amino group and carbon skeleton of amino acids are processed.

Inherited Deffects Of Urea 

a deficiency of any of the urea cycle enzyme would result in hyperammonemia. the condition is more servers when servere  when one of the earlier steps is bloked because ammonia itself gets accumulated and pathway result in accumulation of other intermediates of the cycle as these intermediates are less toxic so is the severity of the condition. hyperammonemia is less severe in those with a partial deficiency. with the exception of OTC (X-linked gene )all genes encoding enzymes and transporters of urea cycle are present on autosomes.

The initial symptoms of hyperammonemia in a child are non specific such as failure to feed, frequent vomiting ,loss of thermoregulation and later lethargy and behavioural abnormalities and irreversible brain damage. the terminal stages of ammonia toxicity leads to coma and eventually death.

tha toxic effect of hyperammonemia may be due to the following reasons ,although complete understanding of the molecular basis is still lacking.

(a) Excessive amount of a-ketoglutarate from citric acid cycle is used to from glutamate and then glutamine. both these reaction consume ammonia the synthesis of glutamate by GDP uses a-ketoglutarate. this result in depletion of a-ketoglutarate for krebs cycle and thereby decreasesed production of ATP.

(b) Both glutamate and GABA are neurotransmitters. the level of these inhibitory neurotransmitters is decreased as more and more glutamate is converted to glutamine.

(c) An increase in the glutamine produces osmotic effects leading to cerebral oedema (swelling) due to increase uptake of water.

A increase of treatment are in use to handle hyperammonemia and specific urea cycle defects. since most of the steps of urea cycle defects. since most of the steps of urea cycle are physiologically irreversible ,the deficient /missing enzyme can be generally identified by determining the intermediate whose level is significantly elevated in blood and urine facilitating specfic treatment.

One of the strategies for coping up with hyperammonemia is to feed orally preparation of sodium benzoate and phenyl butyrate /acetate for long term management. in acute episodes they are infused intravenously. the treatment works by indirectly consuming ammonia. sodium benzoate is activated to benzoyl COA and then conjugated to glycine forming a non toxic product, hippuric acid which is excreted in urine. glycine (a non essential amino acid )is then replenished  by glycine synthesis reaction that consume ammonia. similarly phenyl butyrate is converted to phenyl  acetate by b-oxidation and phenyl acetylcoa  is complexed with glutamine forming phenylacetylglutamine which is excreted. the loss of complexed with glutamine forming phenylacetylglutamine which is excreted. the loss of glutamine is overcome by its synthesis from glutamate and ammonia. 

 

The other therapies are targeted to specific defects ,for examples an arginine succinate deficiency is bypassed by providing surplus arginine and restriction total protein intake. this will fulfill both arginine requirements and generate ornithine for the cycle to continue.