A 27- year-old semi professional tennis player seeks advice from a hospital -based nutritionist concerning his diet supplements. His coach had given him amino acid supplements consisting of phenylalanine and tyrosine. The rationale was that these precursors to several neurotransmitters will “help his brain focus” on his game. In reality, the excess amino acids are used for energy, with a poor and eclectic diet. Phenylalanine upon metabolism, enter TCA cycle as which of the following?
C) Succinyl Co A
E) α- Ketoglutarate
The correct answer is- Fumarate.
Phenylalanine is both glucogenic as well as a ketogenic amino acid. Upon metabolism Phenylalanine forms Fumarate, representing the glucogenic component and Acetoacetate that represents its ketogenic component.
Overview of Phenylalanine metabolism
Phenylalanine is metabolized through formation of Tyrosine. Tyrosine is subsequently metabolized through various pathways forming a number of important biological compounds.
Main pathway of catabolism
The metabolism proceeds through various steps.
1) Step-1- Hydroxylation of Phenylalanine (figure-1 and 2)
i) Enzyme-Phenylalanine hydroxylase
ii) Coenzyme- Tetrahydrobiopterine (BH4)
iii) Product- Tyrosine
Figure-1- Hydroxylation of phenylalanine to tyrosine.
Phenylalanine hydroxylase catalyzes the hydroxylation of phenylalanine to tyrosine. Phenylalanine hydroxylase inserts one of the two oxygen atoms of O2 into phenylalanine to form the hydroxyl group of tyrosine; the other oxygen atom is reduced to H2O. This is one of a general class of reactions catalyzed by enzymes called mixed-function oxidases, all of which catalyze simultaneous hydroxylation of a substrate by O2 and reduction of the other oxygen atom of O2 to H2O. The cofactor, tetrahydrobiopterine is oxidized to dihydrobiopterin during the course of the reaction, which is subsequently reduced again by the enzyme dihydrobiopterin reductase in a reaction that requires NADH/NADPH.
iv) Clinical significance
Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor causes accumulation of phenylalanine in body fluids and the central nervous system (CNS); a condition called Phenylketonuria (PKU). Loss of this enzyme results in mental retardation, organ damage, and unusual posture and can, in cases of maternal PKU, result in severely compromised pregnancy.
2) Step-2- Transamination of Tyrosine
i) Enzyme- Tyrosine aminotransferase
ii) Coenzyme- B6-Phosphate
iii) Product- p-OH- Phenyl Pyruvic acid
The amino group of Tyrosine is transferred to α-Ketoglutarate forming Glutamate, and Hydroxy phenylpyruvate (figure-2), a keto acid of Tyrosine.
iv) Clinical Significance
The deficiency of Tyrosine aminotransferase causes Tyrosinemia type 2, a defect characterized by excessive accumulation of unmetabolized Tyrosine in body fluids and tissues.
Figure-2- Reactions of metabolism of phenylalanine showing the formation of fumarate and Acetoacetate as the end products, representing the glucogenic and ketogenic components respectively.
3) Step-3- Oxidative decarboxylation
i) Enzyme- p-OH Phenylpyruvate Dioxygenase
ii) Product- Homogentisic acid
p-OH Phenylpyruvate undergoes oxidative decarboxylation forming Homogentisic acid. The enzyme incorporates both atoms of oxygen into the substrate, therefore called Dioxygenase.
iii) Clinical significance
Deficiency of – p-OH Phenylpyruvate Dioxygenase, causes Tyrosinemia type-3, a rare genetic disorder.
NTBC (2-Nitro-4-trifluoromethylbenzoyl] cyclohexane-1, 3-dione, is an inhibitor of p-hydroxy pyruvate Dioxygenase, a drug used to treat Tyrosinemia Type-I (see below).
4) Ring cleavage- step-4
i) Enzyme- Homogentisate Dioxygenase
ii) Coenzyme- Vitamin C
iii) Product- Maleylacetoacetate
Ring cleavage by Homogentisate Dioxygenase uses a third molecule of oxygen forming Maleylacetoacetate.
The deficiency of Homogentisate Dioxygenase causes Alkaptonuria, a disease characterized by darkening of urine upon standing, and staining of cartilages and soft connective tissue. The deficiency of vitamin C can also mimic the condition of Alkaptonuria in growing children or infants.
i) Enzyme- Maleylacetoacetate isomerase
ii) Coenzyme- GSH (reduced Glutathione)
iii) Product- Fumarylacetoacetate
Maleylacetoacetate isomerase produces fumarylacetoacetate, in a reaction requiring reduced G-SH.
6) Hydrolytic cleavage
i) Enzyme- Fumaryl acetoacetate Hydrolase
ii) Products- Fumarate and acetoacetate
Fumaryl acetoacetate Hydrolase releases fumarate and acetoacetate.
Fumarate enters TCA cycle to be metabolized further, whereas Acetoacetate is used as a precursor of ketone bodies after getting converted to Acetyl co A.
iii) Clinical significance
Deficiency of Fumaryl acetoacetate Hydrolase causes Tyrosinemia Type-I
Tyrosine can undergo other metabolic pathways producing melanin, catecholamines, thyroid hormone, phenols, cresols, sulfated tyrosine or Tyramine depending upon the cell type or cellular requirement.
In the given case Phenylalanine and tyrosine supplementations can be helpful in providing:
i) Energy through both of its end products, Fumarate and Acetyl Co A involving TCA cycle
ii) Glucose– Fumarate can be converted to oxaloacetate that can be channeled towards the pathway of gluconeogenesis.
iii) Ketone bodies- During periods of intense exercise, or in state of dietary glucose deprivation, ketone bodies released from its metabolism can provide energy alternatively
iv) Neurotransmitters– Nor-epinephrine and epinephrine (catecholamines), produced from Tyrosine can help to boost brain functions.
As regards other options
All of the metabolites, mentioned in the exercise, are intermediates of TCA cycle, but are not produced from the metabolism of phenylalanine. Fumarate is the only metabolite produced from Phenylalanine, and hence it is the correct answer.
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