Biochem CIS - Heck - SRS Flashcards
In the fed state, aa’s are brought in by digestion and travel to the liver. What is nitrogen necessary to synthesize?
Proteins, especially Albumin.
Amino Acids for tissues
What are the carbon portions of the dietary aa’s used for?
Glucose, ketone bodies, triacylglycerols (stored or transported to other tissues)
In the fasting state, where do aa’s come from?
protein breakdown (muscle degredation)
When protein is broken down in the fasting state, some are released directly into the blood. Some lose the nitrogen to glutamine or alanine to be shuttled through the blood.
What does glutamine deliver to the kidney?
What does alanine deliver to the liver?
Ammonia to the urine in the kidney
Nitrogen for urea to the liver
What gives a patient clay colored stools?
Hepatic or bile duct obstruction - decreased bile salts and bilirubin to the intestine
In adults, what is hyperammonemia caused by?
Liver failure
What a consequence of the toxic effects of ammonia?
What are two ways the body tries to compensate for this?
- Brain swelling d/t osmotic imbalance
- High ammonia and glutamate in astrocytes
- Astrocytes producing glutamine
- decreaed glutamate concentration
Astrocytes produce glutamin from alpha-ketoglutarate and ammonia, this exacerbates the osmotic imbalance in the case of hyperammonemia.
What happens at very high glutamine concentrations?
Opens mitochondrial permeability transition pore.
What kind of NT is glutamate?
Excitatory
Glutamate is central to the production of urea, and can provide a nitrogen via two mutually exclusive pathways. Where do each of these nitrogens go to?
One in ammonium ion
one in aspartate
Where does the nitrogen in the ammonium ion come from?
Transamination of other aa’s followed by glutamate dehydrogenase reaction
Where does the nitrogen from aspartate come from?
Glutamate transaminates oxaloacetate (aspartate’s corresponding alpha-keto acid) to aspartate
What does the transamination reaction do?
How is glutamate converted to ammonia?
Is this reversible?
By glutamate dehydrogenase
Is reversible
What are some “other” sources of ammonia?
- deamination of other aa’s
- purine nucleotide cycle in the brain and muscle
- bacteria in the gut
Fill in the blanks in this depiction of the transamination reaction!!!!
In muscle, glucose is metabolized via glycolysis, producing pyruvate.
What transaminates pyruvate?
What does it become?
Glutamate transaminates pyruvate to form alanine
What is alanine used for?
One of two main nitrogen carriers in the blood
What is the other main carrier of nitrogen in the blood besides alanine?
Glutamine
How does glutamate become glutamine?
Accepts a second nirtogen
What is the conversion of glutamate to glutamine used for in the liver?
Liver: to prevent any ammonia that escaped urea production from leaving the liver.
The urea cycle occurs in the liver, what parts of the hepatocytes does this take place in?
Mitochondria
Cytosol
Nitrogen enters the urea cycle as ammonium ion, or aspartate. what happens in the mitochondria?
- Ammonium ion is used to form carbamoyl phosphate
- reacts with ornithine to produce citrulline
- transported to cytosol
Once citrulline is transported to the cytosol in the urea cycle, what then occurs?
- aspartate reacts with citrulline
- arginine is generated
- arginine is cleaved to release urea and regenerate ornithine
If a defect exists in the urea cycle, substrates will accumulate prior to the blockade. This will change the extent of elevation of glutamine and ammonia.
If you have a patient with…
Citrulline - LOW
Urine orotate - LOW
Blood arginine - LOW
Blood NH3 - High
What enzyme is defective?
Carbamoyl phosphate synthetase
If you have a patient with the following…
Urine orotate - High
Blood citrulline - LOW
Blood arginine - LOW
Blood NH3 - High
What is the enzyme defect?
Ornithine transcarbamoylase
If a defect exists in the urea cycle, substrates will accumulate prior to the blockade. This will change the extent of elevation of glutamine and ammonia.
If you have a patient with…
Citrulline - High (>1000 um)
Blood arginine - LOW
Blood NH3 - High
What enzyme is defective?
argininosuccinate synthetase
If a defect exists in the urea cycle, substrates will accumulate prior to the blockade. This will change the extent of elevation of glutamine and ammonia.
If you have a patient with…
Citrulline - High (200um)
Urine orotate - LOW
Blood arginine - LOW
Blood NH3 - High
What enzyme is defective?
Argininosuccinate lyase
If a defect exists in the urea cycle, substrates will accumulate prior to the blockade. This will change the extent of elevation of glutamine and ammonia.
If you have a patient with…
Blood arginine - High
Blood NH3 - moderately High
What enzyme is defective?
Arginase
Carbamoyl phosphate is created in the mitochondria, what does it do?
Allows ammonia to enter the urea cycle.
When does carbamoyl phosphate accumulate?
When ornithine transcarbamoylase is deficient.
In the event of an ornithine transcarbamoylase is deficient What happens to the excess carbamoyl phosphate?
Enters pathway for pyrimidine biosynthesis
Once carbamoyl phosphate enters the pyrimidine synthesis pathway what does it become?
Orotic acid
Orotate
What is elevation of orotate and orotic acid in the urine indicative of?
Urea cycle defect
What is the difference between homocysteine and homocystine?
Homocysteine - amino acid
Homocystine - dimer of homocysteine
What are the categories of amino acid degredation products?
Glucogenic
Ketogenic
Both
Glucogenic degredation leads to carbons being used to create glucose in the liver, and produces intermediates of the TCA cycle.
What AA’s are used to produce glucose?
All non-essential aa’s
In ketogenic degredation of aa’s carbons are used to create ketone bodies or their precursors, e.g. acetyl-coa or acetoacetate.
What aa’s are strictly ketogenic?
Lysine
Leucine
What aa’s have degredation products that can be classified as both glucogenic and ketogenic?
- Tryptophan
- isoleucine
- threonine
- phenylalanine
- tyrosine
What is the inheritance pattern of homocystinuria?
Autosomal recessive
What is deficient in homocystenuria?
Cystathione synthase
How does homocystenuria present clinically?
- Cardiovascular disease
- DVT
- Thromboembolism
- Stroke
- Dislocation of the lens (Downward)
- Mental retardation
- marfanoid habitus
Homocystenuria presents with characteristically deficient levels of what?
cysteine
What substrates accumulate in homocystinuria?
Methionine
homocysteine
In B12 and folate deficiency what are serum methionine levels like?
Low
What coenzymes are involved in the urea cycle?
B12
Folate
B6 (pyridoxal phosphate)
What is B6 a key coenzyme for?
AA metabolism
What is B6 required for?
Transamination rxns
What is given to treat homocystinuria?
B6 (pyridoxal phosphate)
Describe the metabolism of alcohol.
Ethanol rapidly converted to acetaldehyde in liver, then converted to acetate
What do the two rxns in metabolism of etoh require?
NAD+
What is NAD+ also required for?
Gluconeogenesis
What does an alcoholic, based on the NAD+ requirements for etoh metabolism, have an increased risk of?
Hypoglycemia, NAD+ is consumed, and gluconeogensis is not possible because the increased [NADH]/[NAD+] drives the pathway backwards and prevents lactate, alanine and glycerol from entering the pathway.
what causes wernicke’s encephalopathy?
What is the presentation?
Thiamine deficiency
Oculomotor dysfunction and gait ataxia
What two processes mantain blood glucose levels?
