Branched Chain/Sulfur -Containing Amino Acid Metabolism Flashcards
What are the three branched chain amino acids
leucine, isoleucine and valine.
What are the wo common enzymes that begin the common catablism of branched chain AA
BCAA Aminotransferase and BC Alpha-Keto Acid Dehydrogenase
Function of BCAA aminotransferase and where is it active
BCAA aminotransferase is a transaminase enzyme that coverts BCAA into branched chain α-keto acids (BCAKA)
BCAA aminotransferase is highly active in skeletal muscle but not liver
What is BCAKA dehydrogenase
BC Alpha-Keto Acid Dehydrogenase
BCAKA dehydrogenase is located in the mitochondrial inner membrane and is analogous to the pyruvate dehydrogenase complex
BCAKA dehydrogenase is a large mitochondrial multi-enzyme complex.
The complex is composed of a decarboxylase (E1) with two α and β subunits, a transferase (E2), and a dehydrogenase (E3).
BCAKA dehydrogenase catalyzes the oxidative decarboxylation of BC α-keto acids forming NADH, CO2, and a corresponding hydrocarbon product linked to CoA.
Where is BCAKA high
Branched chain keto acids (BCKA) formed by transamination are transported from skeletal muscle to the liver where the activity of BCAKA dehydrogenase is high
Thus, catabolism is initiated in skeletal muscle but completed in the liver.
BCAKA dehydrogenase is most active in the muscle during starvation.
Clinical features of classic maple sugar urine disease
The clinical features of MSUD are largely dependent on the amount of residual BCAKA dehydrogenase activity present in a patient. For classical MSUD, patients have from 0-3% of the normal amounts of BCAKA dehydrogenase activity.
Clinical features for classic MSUD include:
neonatal onset
maple syrup odor
poor feeding
Irritability, lethargy
opisthotonus (severe hyperextension, spasticity), focal dystonia
“Fencing,” “bicycling”
Other forms of MSUD with up to 30% of normal BCAKA dehydrogenase activity show milder and more variable expression of the clinical features observed in classic MSUD. Metabolic stress caused by illness or poor feeding, which induce catabolic states can lead to neurologic deterioration in patients with milder forms of MSUD.
Genetics and epidemiology of MSUD
At least six nuclear genes encode components of the BCAKA dehydrogenase complex;
3 of these genes account for almost all cases of MSUD.
MSUD is relatively rare in the general population, affecting ~1 in 200,000 individuals.
Mennonites have an increased incidence, ~1 in 200, due to a founder mutation that causes an amino acid substitution in one of the subunits of BCAKA dehydrogenase.
Treatment for MSUD
Low protein diet with restriction of leucine (Leu), isoleucine (Ile), and valine (Val). Adding medical formula, supplements (BCAAs are essesntial AAs)
Thiamine supplements
The first step in the oxidative decarboxylation of the BCAA catalyzed by BCAKA dehydrogenase involves thiamine pyrophosphate as a coenzyme.
Some patients with residual enzyme activity respond to thiamine supplements, restoring activity to levels that ameliorate symptoms
Monitoring for MSUD
Plasma levels of BCAA need to be monitored on a regular basis to assess the delicate balance of providing sufficient essential amino acids to support normal growth or development without having excess BCAA or BCAKA accumulate to toxic levels.
Urine levels of BCAKAs if high can indicate a catabolic state and insufficient metabolic control indicating a need for change in treatment plan
Final breakdown products of BCAAs
Valine is ultimately broken down to propionyl-CoA which is glucogenic
Isoleucine gives rise to acetyl-CoA and propionyl-CoA and is therefore, ketogenic and glucogenic, respectively.
Leucine follows a path through hydroxymethylglutaryl- CoA which is cleaved to acetyl-CoA and acetoacetate. Leucine is strictly ketogenic.
The branched chain amino acids have large hydrocarbon side chains. SImilar to fatty acids
What is Propionyl-CoA Carboxylase
Works in the breakdown of valine anad isoleucine
converts propionyl-CoA to D-methylmalonyl-CoA (Fig. 2)
catalyzes a carboxylase reaction that employs biotin as a coenzyme
is a mitochondrial enzyme with 12 subunits, 6 alpha chains and 6 beta chains.
What are the sources of proprionic acid
VOMIT
These include the amino acids:
valine
isoleucine
methionine
threonine.
Another source of propionic acid, though in lesser amounts than from the catabolism of the amino acids shown, is the breakdown of:
odd chain fatty acids.
Clinical features of Propionic Acidemia
Severe forms of propionic acidemia present in the newborn period.
Symptoms include:
poor food intake and vomiting
lethargy
hypotonia
seizures
coma.
Labs for proprionic acidemia
Wide anion gap (metabolic acidosis)
Elevated propionic acid and glycine in blood
Ammonemia
How does proprionic acidemia lead to high ammonia levels
propionic acid inhibits N-acetylglutamate synthase, reducing levels of N-acetylglutamate, which reduces the activity of carbamoyl phosphate synthetase I, which in turn, shuts down the urea cycle, leading to hyperammonemia.
Genetics of proprionic acidemia
Primary cause - deficiency of propionyl-CoA carboxylase
Autosomal recessive disorder linked to mutations in genes encoding alpha and beta subunits.
Secondary causes
Deficiency of biotin uptake and utilization
Classified as multiple carboxylase deficiency as other carboxylase enzymes using biotin as a coenzyme are also affected
Deficiency of L-methyl malonyl-CoA mutase can lead to increased levels of both methylmalonic acid and propionic acid.
Treatment for proprionic acidemia
Coenzyme supplementation - Value of biotin therapy variable, Patients with multiple carboxylase deficiency are often biotin responsive, Patients with elevated propionic acid due to a deficiency of L-methyl malonyl-CoA mutase may respond to vitamin supplementation with B12.
Dietary protein restriction
Carnitine supplements - propionic acid bound to propionyl-CoA can be transferred to carnitine and excreted in urine
Antibiotics - Antibiotics are administered to reduce propionic acid synthesis from intestinal bacteria,
What is L-Methylmalonyl-CoA Mutase
Converts L-methylmalonyl-CoA to succinyl-CoA (Fig. 2)
The methylmalonic acid mutase reaction requires vitamin B12
How is glycine synthesized
Glycine is derived from serine, which in turn, is derived from the glycolytic intermediate 3-phosphoglycerate making both serine and glycine non-essential amino acids.
Glycine is derived from serine in a reaction catalyzed by serine transhydroxymethylase. Reversible
Fates of glycine
Conversion back to serine (the direction of this reaction is dictated by the needs of a cell at any particular instant in time).
Another fate for glycine is its degradation via a pathway initiated by D-amino acid oxidase, which forms glyoxylate and then gets converted to oxalate.
Oxalate is sparingly soluble and can precipitate in the kidney and is a source of kidney stones.
Breakdown into CO2
Steps in the breakdown of methionine
The breakdown of methionine begins with the formation of S-adenosylmethionine (AdoMet or SAM) This reaction is catalyzed by methionine adenosyltransferase.
The substrates for this reaction are methionine and ATP.
All of the phosphates of ATP are lost in the formation of the product, AdoMet.
AdoMet is used as a methyl group donor in a wide range of biochemical reactions. The product of these methyltransferase reactions is S-adenosylhomocysteine (Fig. 4B).
S-adenosylhomocysteine is subsequently cleaved to adenosine and homocysteine.
Role of Cystathionine Synthase
Cystathionine synthase catalyzes the reaction where homocysteine condenses with serine to form cystathionine.
Cystathionine synthase is a pyridoxal phosphate-dependent enzyme that is feedback inhibited by cysteine.
Steps for breakdwon of cystathionine
The next reaction in the pathway is catalyzed by cystathionase which converts cystathionine to cysteine.
Cystathionase is also a pyridoxal phosphate-dependent enzyme.
In the transulfuration reaction catalyzed by cystathionase, the sulfur of homocysteine is transferred to the carbon skeleton of serine forming cysteine.
The other product of the cystathionase reaction is α-ketobutyrate, which goes on to form succinyl-CoA
Cysteine can be further metabolized to pyruvate and sulfate.
Both pyruvate and succinyl-CoA can give rise to gluconeogenic substrates, making both methionine and cysteine glucogenic amino acids.
What is the remethylation pathway
The remethylation pathway gets its name because it is where homocysteine can be methylated back to methionine.
not a reversal of the pathway by which methionine is converted to homocysteine.
What is the alernative remethylation pathway
second remethylation pathway using betaine as a methyl group donor.
Role of Methionine Synthase in folate and B12
the remethylation pathway as the critical intersection point between B12 and folic acid metabolism. The reaction catalyzed by methionine synthase is one of two B12-dependent reactions in the human body
Methyl-cobalamin is the methyl group donor for the methionine synthase reaction.
Methionine synthase creates methyl-cobalamin at its active site by transferring a methyl group from N5-methyl-tetrahydrofolate to cobalamin.
The transfer of the methyl group from N5-methyl-THF to cobalamin by methionine synthase is the only reaction of intermediary metabolism that consumes N5-methyl-THF.
What are the various sources of one carbon derivatives of tetrahydrofolate
You see one carbon units coming from serine, glycine, histidine, and tryptophan.
These one carbons units are used in purine synthesis and thymidylate synthesis
What is the folate trap
The derivatives N5,N10-methylene-THF, N5,N10-methenyl-THF, and N10-formyl-THF are all in equilibrium with one another.
The exception to the equilibration of THF derivatives is N5-methyl-THF, as the reaction catalyzed by methyltetrahydrofolate reductase is irreversible.
The only way to get N5-methyl-THF back into the pool of folate metabolites is through the methionine synthase reaction.
If the methionine synthase reaction is inhibited, folate pools drain into the production of the now dead end intermediate N5-methyl-THF, depleting all other THF
Mechanism behind folate trap
One way that methionine synthase is inhibited is insufficient amounts of B12.
Thus, a B12 deficiency also manifests as a folic acid deficiency.
This intersection of B12 and folic acid metabolism is known as the folate trap, where low levels of B12, trap folic acid as the dead end intermediate N5-methyl-THF.
