Urea Cycle and Disease

by Kevin Ahern, PhD

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    00:02 Now, urea cycle relates to a lot of things in human disease.

    00:06 We've already seen several examples.

    00:08 It is believed to be very underdiagnosed in infant death.

    00:12 And it may represent as much as 20% of all the sudden infant death syndrome deaths that occur.

    00:18 For people who have the non-lethal form, problems can be focused on the accumulation of ammonia or also on citric acid cycle intermediates.

    00:26 And both of those actually occur.

    00:29 So, these tables I'll show in the next two slides depict some of the urea cycle diseases and some of the effects of those.

    00:36 In each case the enzyme I'm describing as deficient is one of the five enzymes that we started with in the feeder reaction or the urea cycle.

    00:45 The carbamoyl phosphate synthethase was the enzyme of the feeder reaction.

    00:49 Deficiency of it leads to the disease carbamoyl phosphate synthethase I deficiency, which the name is pretty much describing exactly what's happening.

    00:57 And the molecule that accumulates in this case is ammonium.

    01:01 The ammonia of course was produced by the catabolism of amino acids.

    01:05 So, if this can't be made into carbamoyl phosphate, ammonia will accumulate.

    01:09 The symptoms of this disease include developmental delay and mental retardation Ornithine transcarbamylase catalyzes that first reaction of the urea cycle.

    01:20 And its name also like the other one is ornithine transcarbamylase deficiency and that also describes exactly what has happened here.

    01:30 The molecules that accumulate with the deficiency of this enzyme include ornithine, uracil and orotic acid.

    01:37 Now, the symptoms of this disease are pretty severe.

    01:40 We're talking about death and seizures in the severe cases.

    01:43 But in adults, if it's an adult onset, there's a very wide spectrum of results and in some cases can actually be managed with diet.

    01:50 The argininosuccinate when it's deficient leads to argininosuccinate acidemia.

    01:56 The molecule that accumulates here is the precursor that can't be converted by the enzyme and that's citrulline.

    02:03 In addition to citrulline, ammonia as is true of all of these enzyme deficiencies accumulates.

    02:08 Symptoms of the disease include lethargy, seizures, liver damage, and in some case coma especially among young people.

    02:17 Argininosuccinate lyase when it's deficient, results in argininosuccinic aciduria and the molecules that accumulate here are citrulline from two reactions before and argininosuccinic acid which is the substrate for this enzyme.

    02:32 Deficiencies result in the symptoms of lethargy, lack of appetite, again coma and mental retardation and again the more severe effects occurring when the children start with the disease.

    02:45 And the last enzyme arginase, as I said, is the one that is the least likely to be deficient.

    02:50 It is a disease that creates -- it's a deficiency that creates the disease argininemia and the molecule that accumulates is arginine.

    02:58 Now, the symptoms here seem a little less severe.

    03:02 It may result in leg stiffness and in some cases slow growth or developmental delay.

    03:07 In more severe cases, seizures may result.

    03:11 The treatment for all of these diseases is the same, balancing protein intake.

    03:16 Because the more protein and the more amino acids you have, the more likely you're going to have to balance and get rid of more of those ammonia and ammonium ions.

    03:26 There are medications in some cases to favor the movement of accumulating molecules to other alternative pathways.

    03:33 And in severe cases, liver transplants can help a person to lead and live a normal life.

    About the Lecture

    The lecture Urea Cycle and Disease by Kevin Ahern, PhD is from the course Amino Acid Metabolism.

    Included Quiz Questions

    1. Ornithine transcarbamylase — Carbamoyl phosphate deficiency
    2. Argininosuccinate lyase — Argininosuccinic aciduria
    3. Carbamoyl phosphate synthetase — Carbamoyl phosphate synthetase I deficiency
    4. Argininosuccinate synthetase — Citrullinemia
    5. Arginase — Argininemia
    1. Arginase — Urea
    2. Argininosuccinate lyase — Argininosuccinic acid and citrulline
    3. Carbamoyl phosphate synthetase — Ammonia
    4. Argininosuccinate synthetase — Citrulline
    5. Ornithine transcarbamylase — Ornithine, uracil, and orotic acid

    Author of lecture Urea Cycle and Disease

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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