Nitrogen Elimination and Carbon Chain Metabolism II Flashcards
The initial step in urea synthesis occurs in the mitochondria, and requires 2 ATP’s per urea. Note that the ATP is hydrolyzed in two distinct steps that generate
Pyrophosphate and then inorganic phosphate
The α-NH3 from most amino acids is transferred to α-ketoglutarate. The sole purpose of this mechanism is to concentrate all the α-NH3 groups, from different amino acids, predominantly into
Glutamate
Although this does not reduce the overall levels of nitrogen, it permits a single enzyme, glutamate dehydrogenase, to release nitrogen from glutamate and initiate the formation and excretion of
Urea
Non-specific proteases, such as those expressed in the gut can be extremely deleterious to other
Cellular proteins
Glutaminase, Asparaginase and glutamate dehydrogenase release ammonia from
Glutamine, asparagine, and glutamate respectively
Reduced expression of N-acetylglutamate could result in
Ammonia toxicity
Reduced expression of N-acetylglutamate could result in ammonia toxicity. This defect could be severe in individuals with liver disease. This toxicity could be exacerbated by a
High protein diet
Amino acids are classified as being either
Glucogeninc or ketogenic
Channeled into pyruvate or other TCA intermediates, and can be fully catabolized, or can be used for the formation of glycogen
Glucogenic amino acids
Terminate as acetyl-CoA or its derivatives, and the energy yield is lower
Ketogenic amino acids
Glucogenic amino acids can also produce acetyl-CoA, although the important distinction is that the ketogenic amino acids do not enter
TCA
The synthesis of cysteine requires
Methionine
The production of tyrosine requires
Phenylalanine
A high-energy and unstable compound, containing a CH3 group that is linked to a sulfur atom in methionine
SAM
The methyl group in SAM is transferred rapidly to
DNA, RNA, and hormones
After the methyl group has been contributed to a reaction, the resulting S-adenosyl-homocysteine can be converted back to
Methionine
This reaction requires the co-factor methylcobalamin and
Methyltetrahydrofolate
Derived from vitamin B12
Methylcobalamine
Homocysteine can also be converted to cysteine, in a reaction that requires
Pyridoxal phosphate/vitamin B6
An essential vitamin that performs in single carbon donor reactions
Folate
Can receive carbon from a variety of different donor molecules, and based on the chemical form, distinct bonds are formed with its nitrogen atoms
Tetrahydrofolate
Carbonic acid is the hydrated form of CO2, and is transported by
Biotin
You should recognize that a defect in enzymes that form either carbamoyl phosphate (ie: carbamoyl phosphate synthase I), or stimulate its activity by N-acetylglutamate (N-acetylglutamate synthase) could have
Similar negative effects
Carbamoyl phosphate synthase I defects / N-acetylglutamate synthase defects result in the accumulation of
Ammonia
Given the extreme toxicity caused by ammonia to the CNS, defects in these pathways can cause severe cognitive deficiencies
Carbamoyl phosphate synthase I defects / N-acetylglutamate synthase defects
Can breach the permeability across the hepatocyte cell membrane, and release transaminases into circulation
Liver disease
A common genetic defect (1/15,000 incidence) that causes accumulation of phenylalanine, and reduces the synthesis of tyrosine
Phenylketonuria (PKU)
Although there are multiple causes for PKU, the classic form results from a defect in the enzyme
Phenylalanine hydroxylase (PAH)
Functions to convert phenylalanine to tyrosine
PAH
Failure to convert phenylalanine to tyrosine results in the accumulation of phenylalanine and other byproducts, and is accompanied by progressive
Mental retardation
Phenylalanine hydroxylase requires a cofactor called
-Defects in the synthesis of this cofactor can also cause PKU
Tetrahydrobiopterin
Large neutral amino acid transporters are required for transport of phenylalanine and certain other amino acids across the
Blood-brain barrier
However, high levels of phenylalanine can competitively block the entry of other neutral amino acids into the
Brain
Required for the synthesis of the pigment melanin
Tyrosine
PKU patients tend to be faired and frequently have
Greener eyes
Specific amino acid transporters in the kidney can reabsorb amino acids in the urine. However, defects in specific transporters can lead to high levels of certain amino acids in the blood
Blue-diaper syndrome
For instance, accumulation of tryptophan, as a result of an absorption defect in the intestine, results in its degradation by intestinal bacteria, and the generation of
Indole
Following oxidation indole is converted to indigo blue, which is excreted in the urine, and stains the diaper
Blue
This is a rare, autosomal recessive trait that is accompanied by digestive problems and visual impairment
Blue-diaper syndrome
A rare disease that is caused by the failure to remove the α-amino group from tyrosine
Aminotransferase defect. Type II tyrosinemia
Aminotransferase defect. Type II tyrosinemia is a rare disease that is caused by the failure to remove the α-amino group from tyrosine. The defect lies in the gene encoding
Tyrosine aminotransferase
Aminotransferase defect. Type II tyrosinemia causes accumulation of tyrosine, and is associated with
Mental retaration and defects in the eyes and skin
One of the most frequently occurring genetic defects (~1/10,000)
Polycystic Kidney Disease (PKD)
Incurable, and is associated with the formation of fluid filled cysts in both kidneys
Polycystic Kidney Disease (PKD)
Polycystic Kidney Disease (PKD) is also associated with an
Auto immune effect
Adult symptoms of PKD include
Fatigue, headaches, UTI, and hypertension
Individuals with advanced disease have a high incidence of
Kidney stones and liver damage
The final phase, that leads to death, is caused by
-results from complete renal failure
Uremia
Treatment for PKD might include reducing blood pressure (antihypertensive meds / diuretics / low salt diet), close monitoring for infection caused by hernia, antibiotic therapy to suppress inflammation and infusion of
RBC
