Term
| How does ammonia enter the urea cycle? |
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Definition
The reaction of NH4 and bicarbonate to form carbamoyl phosphate
This step requires 2 equivalents of ATP and the mitochondrial matrix enzyme carbamoyl phosphate
synthetase-I (CPS-I).
The allosteric effector N-acetyl-glutamate positively regulates CPS-I
The steady-state concentration of N-acetylglutamate is set by the concentration of its components acetyl-CoA and glutamate and by arginine, which is a positive allosteric effector of N-acetylglutamate synthetase |
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Term
| How is citrulline formed in the urea cycle? |
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Definition
Ornithine arising in the cytosol is transported to the mitochondrial matrix, where ornithine transcarbamoylase (OTC) catalyzes the condensation of ornithine with carbamoyl phosphate, producing citrulline.
The energy for the reaction is provided by the high-energy anhydride of carbamoyl phosphate. The product,citrulline, is then transported to the cytosol |
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Term
| How is argininosuccinate formed in the urea cycle? |
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Definition
In a 2-step reaction, catalyzed by cytosolic argininosuccinate synthetase, citrulline is converted to argininosuccinate.
The reaction involves the addition of AMP (from ATP) to the amide carbonyl of citrulline, forming an activated intermediate on the enzyme surface (AMP-citrulline),
and the subsequent addition of aspartate to form argininosuccinate |
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Term
| How are arginine and fumarate produced in the urea cycle? |
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Definition
| Arginine and fumarate are produced from argininosuccinate by the cytosolic enzyme argininosuccinate lyase (also called argininosuccinase). |
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Term
| How is urea formed in the urea cycle (last step)? |
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Definition
| In the final step of the cycle arginase cleaves urea from arginine, regenerating cytosolic ornithine, which can be transported to the mitochondrial matrix for another round of urea synthesis. |
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Term
| Where does the aspartate used in the argininosuccinate synthetase reaction come from? |
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Definition
| The fumarate, generated via the action of argininosuccinate lyase, is reconverted to aspartate for use in the argininosuccinate synthetase reaction. This occurs through the actions of cytosolic versions of the TCA cycle enzymes, fumarase (which yields malate) and malate dehydrogenase (which yields oxaloacetate). The oxaloacetate is then transaminated to aspartate by AST |
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Term
| What are the general symptoms associated with urea cycle disorders? |
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Definition
neurologic deficits
ataxia
death (if untreated) - speed depends on deficiency |
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Term
| Explain Type 1 Hyperammonemia |
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Definition
deficiency in Carbamoylphosphate synthetase I
treatment with arginine which activates N acetylglutamate synthetase (enzyme for synthesis of
N acetylglutamate, allosteric activator of CPSI ) |
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Term
| Explain N-acetylglutamate synthetase deficiency |
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Definition
deficiency in N-acetylglutamate synthetase
causes severe hyperammonia
treatment includes administration of carbamoyl glutamate to activate CPS-I |
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Term
| Explain type 2 hyperammonia |
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Definition
deficiency in Ornithine transcarbamoylase (OTC)
most common UCD
treat with high carbohydrate, low protein diet, ammonia detoxification with sodium phenylacetate or sodium benzoate |
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Term
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Definition
deficient in Argininosuccinate synthetase
treat with arginine administration (arginine limiting)
and to enhance citrulline excretion. Also treat with sodium benzoate for ammonia detoxification |
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Term
| Explain Argininosuccinic aciduria |
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Definition
deficient in Argininosuccinate lyase (argininosuccinase)
treat with arginine (limiting) and sodium benzoate |
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Term
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Definition
deficiency in arginase
treatment includes diet of essential amino acids excluding arginine + low protein diet |
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Term
| What does glucogenic mean? |
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Definition
Amino acid catabolism yields pyruvate or citric acid cycle intermediates, which are substrates for glucose
production. |
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Term
| What does ketogenic mean? |
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Definition
Amino acid catabolism yields acetyl CoA or acetoacetyl CoA, which are substrates for ketone body production
from fatty acid oxidation. |
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Term
| What are the main seven products that AA catabolism converge to? |
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Definition
| oxaloacetate, α-ketoglutarate, pyruvate, fumarate, succinyl CoA, Acetyl-CoA and acetoacetyl CoA |
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Term
| What are the purely ketogenic amino acids? |
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Definition
Leucine and Lysine
the two L amino acids |
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Term
| What amino acids are both ketogenic and glucogenic? |
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Definition
Isoleucine
Phenylalanine
Tryptophan
Tyrosine
Threonine
Remember aromatic AA's + isoleucine and threonine |
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Term
| What amino acids are purely glucogenic? |
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Definition
Easiest way to remember, all AA's that aren't purely ketogenic or both ketogenic and glucogenic
ketogenic - lysine and leucine
both - isoleucine, phenylanaline, tryptophan, tyrosine, threonine, |
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Term
| Which amino acids yield OOA? |
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Definition
Asparagine hydrolyzed to aspartate (asparaginase)
Aspartate loses amino group by transamination to form oxaloacetate |
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Term
| Which AA's yield α-ketoglutarate? |
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Definition
Glutamine converted to glutamate by glutaminase. Transamination or oxidative deamination to α-
ketoglutarate
Histidine (helps produce tetrahydrofolate), arginine , proline converted to α-ketoglutarate via glutamate |
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Term
| Which AA's yield pyruvate? |
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Definition
Alanine loses amino group by transamination to form pyruvate - alanine cycle important for generating pyruvate for gluconeogenesis
Serine to pyruvate by direct deamination by serine dehydratase. Water eliminated.
Glycine may be converted to serine then pyruvate or oxidized to CO2 and NH4+
Cysteine undergoes desulfuration to yield pyruvate
Threonine converted to pyruvate or to α-ketobutyrate, which forms succinyl CoA. Has no transamination step, instead dehydrogenase and dehydratase enzymes. (Threonine along with lysine cannot be transaminated) |
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Term
| Which AA's yield fumarate? |
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Definition
Phenylalanine and tyrosine. Hydroxylation of phenylalanine gives tyrosine. Subsequent catabolism of
tyrosine leads to the formation of fumarate and acetoacetate (glucogenic and ketogenic).
There are inherited deficiencies in the enzymes of phenylalanine/tyrosine catabolism. |
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Term
| Which AA's yield succinyl CoA? |
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Definition
Methionine, valine, isoleucine and threonine are converted to propionyl CoA by different pathways.
Propionyl CoA is converted to methylmalonyl CoA then succinyl CoA.
There may be an inherited defect of the enzyme methylmalonyl CoA mutase necessary for the final step to succinyl CoA. |
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Term
| Which Amino acids yield acetyl CoA or acetoacetyl CoA? |
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Definition
Leucine, (exclusively ketogenic) and isoleucine (both ketogenic and glucogenic) are branched chain
amino acids
Lysine exclusively ketogenic. Has unusual metabolism with no transamination step. Forms acetoacetyl
CoA via crotonyl CoA, an intermediate in the β-oxidation of fatty acids.
Tryptophan (ketogenic and glucogenic) yields acetoactyl CoA via crotonlyl CoA. |
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Term
| How are the branched chain AA's metabolized? |
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Definition
Leucine, valine, isoleucine are metabolized primarily by the peripheral tissues, particularly muscle.
They have similar routes of catabolism. After conversions to their corresponding a-ketoacids by
transamination, a common enzyme (branched chain ketoacid dehydrogenase), catalyzes oxidative
decarboxylations.
The three CoA derivatives are then degraded by different pathways to yield different products. |
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Term
| Which AA's are synthesized from glycolytic intermediates? |
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Definition
alanine, serine, glycine, cysteine
Pyruvate > alanine, transamination with glutamate
Serine from 3 phosphoglycerate
Serine > serine hydroxymethyl transferase + FH4 > glycine
Serine > cystothinine synthase > Cystothionine > cystothionase > Cysteine. |
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Term
| Which AA's are synthesized from TCA cycle intermediates? |
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Definition
aspartate, glutamine, asparagine, proline
OAA > glutamate > Aspartate > glutamine > Asparagine
A-KG > NH4+ > Glutamate > + NH4+ glutamine synthase > Glutamine
Glutamate > glut semialdehyde + cyclization > Proline |
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Term
| How is arginine synthesized? |
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Definition
In the urea cycle by argininosuccinate lyase
It is considered a conditional essential AA because this synthesis is very limited |
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Term
| How is tyrosine synthesized? |
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Definition
It is synthesized from phenylanaline
Phenylala > phenylala hydroxilase + tetrahydrobiopterin > Tyrosine |
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Term
| What is the role of pyridoxal phosphate (PLP) in serine and glycine metabolism? |
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Definition
It is used in the conversion of serine to pyruvate
the interconversion of serine and glycine |
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Term
| Vitamin B6, vitamin B12, FH4 (tetrahydrofolate), and tetrahydrobiopterin are co-factors for which respective reactions in AA metabolism? |
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Definition
Vitamin B6 cofactor is pyridoxal phosphate (PLP) - necessary in transamination reactions
Vitamin B12 cofactor is used in catabolism of AA's to succinyl CoA, specifically the step from methylmalonyl CoA to succinyl CoA
FH4 is used in the catabolism of histidine, specifically the step that forms glutamate
FH4 used to make glycine from serine in the serine hydroxymethyl transferase rxn
Tetrahydrobiopterin is used in the reaction of phenylanaline to tyrosine |
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