BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 18. AMINO ACID DEGRADATION AND THE UREA CYCLE

18.15. Leucine is Degraded into Acetyl-CoA and Acetoacetyl-CoA

As mentioned above, leucine is the only purely ketogenic amino acid among the complete set of twenty Amino Acids. It is degraded via reactions we have already encountered when examining Fatty acid oxidation and The Tricarboxylic Acid Cycle. First, leucine undergoes Transamination to yield the corresponding α-keto acid, α-ketoisocaproate. This keto acid is then oxidatively decarboxylated to isovaleryl-CoA. This reaction is analogous to The oxidative decarboxylation of Pyruvate to acetyl-CoA and of α-ketoglutarate to succinyl-CoA.

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Isovaleryl-CoA is dehydrogenated directly to form β-methylcrotonyl-CoA. This oxidation is catalyzed by isovaleryl-CoA dehydrogenase, with FAD serving as the hydrogen acceptor, much like in the analogous fatty acid oxidation reaction catalyzed by acyl-CoA dehydrogenase. Carboxylation of β-methylcrotonyl-CoA in the presence of excess ATP yields β-methylglutaconyl-CoA. As might be expected, the MECHANISM OF ACTION of β-methylcrotonyl-CoA carboxylase is very similar to that of pyruvate carboxylase and acetyl-CoA carboxylase. It is worth noting here that much of our modern understanding of the Mechanism of biotin-dependent carboxylation reactions is due to the work of Feodor Lynen, a pioneer in the research of these Enzymes.

Beta-methylglutaconyl-CoA is then hydrated to form β-hydroxy-β-methylglutaryl-CoA, which is cleaved into acetyl-CoA and acetoacetate. This reaction

has already been discussed in connection with the Formation of Ketone bodies from Fatty acids (Section 17.12). It is interesting to note that The breakdown of leucine into acetyl-CoA and acetoacetate involves numerous Coenzymes: Pyridoxal phosphate in transamination, thiamine pyrophosphate, lipoate, FAD, and NAD⁺ in oxidative decarboxylation, FAD again in dehydrogenation, and biotin in carboxylation. Coenzyme A serves as the acyl carrier in these reactions.

The degradation pathways of valine and isoleucine are similar to that of leucine. All Three amino acids are first transaminated to their respective α-keto acids, which then undergo oxidative decarboxylation to form CoA derivatives. Subsequent reactions mirror those of fatty acid oxidation. Isoleucine yields acetyl-CoA and propionyl-CoA, whereas valine produces methylmalonyl-CoA. There is an inborn error of METABOLISM that disrupts The oxidation of valine, isoleucine, and leucine. In maple syrup urine disease, the Oxidative Decarboxylation of these three amino acids is blocked. As a result, the levels of leucine, isoleucine, and valine in the Blood and urine rise significantly, leading to a corresponding increase in the concentration of their parent α-keto acids. The urine of such patients emits the characteristic odor of maple syrup, which gives the disease its name. Maple syrup urine disease is typically fatal unless affected infants are placed on a diet low in valine, isoleucine, and leucine from an early age.

18.16. Phenylalanine and Tyrosine are Degraded to Acetoacetate and Fumarate by Oxygenases

The degradation pathway of Phenylalanine and Tyrosine possesses several fascinating features. It represents a series of reactions in which molecular oxygen is utilized to cleave the aromatic ring. The first step in this sequence is the hydroxylation of phenylalanine to tyrosine, a reaction catalyzed by phenylalanine hydroxylase. This enzyme is classified as a monooxygenase (also known as a mixed-function oxygenase) because one atom of O₂ is incorporated into the product, while the other is reduced to H₂O.

The reducing agent here is tetrahydrobiopterin, an electron carrier we have not encountered previously. Its oxidized form is dihydrobiopterin.

NADPH reduces dihydrobiopterin to regenerate tetrahydrobiopterin, a reaction catalyzed by dihydrobiopterin reductase. The overall equation for the Reactions Catalyzed by phenylalanine hydroxylase and dihydropterin reductase is as follows:

Phenylalanine + O₂ + NADPH + H⁺ → Tyrosine + NADP⁺ + H₂O.

The next step is the transamination of tyrosine to p-hydroxyphenylpyruvate (Fig. 18.17). This α-keto acid then reacts with O₂ to form homogentisate. The enzyme catalyzing this complex reaction, p-hydroxyphenylpyruvate hydroxylase, is termed a dioxygenase because both atoms of O₂ are incorporated into the resulting product. The aromatic ring of homogentisate is subsequently cleaved by an O₂ molecule to form 4-maleylacetoacetate. This reaction is catalyzed by another dioxygenase, homogentisate oxidase. In fact, nearly all aromatic ring Cleavage processes in biological systems are catalyzed by Dioxygenases, a class of enzymes discovered by Osami Hayaishi. 4-Maleylacetoacetate is then isomerized to 4-fumarylacetoacetate, which is ultimately hydrolyzed into fumarate and acetoacetate.

Fig. 18.17. The degradation pathway of phenylalanine and tyrosine

18.17. Garrod's Discovery of Inborn Errors of Metabolism

Alkaptonuria is an inherited metabolic disorder caused by a deficiency of homogentisate oxidase. Homogentisate accumulates and is excreted in the urine, causing it to turn black upon standing as the homogentisate oxidizes and polymerizes into a melanin-like compound. Alkaptonuria is a relatively benign condition (a mild disorder), as described by Zacutus Lusitanus in 1649:

"The patient was a boy whose urine was blackish in color. At the age of 14, he underwent vigorous treatments aimed at subduing the fiery heat of his internals, which was believed to be the cause of his illness, scorching his humors and turning them black. Among the prescribed measures were bloodletting, purgatives of The Stomach, baths, cold and fluid diets, and a multitude of medicines. None of these measures produced any visible effect, and eventually the boy, weary of useless and excessive treatments, decided to let nature take its course. None of the ominous predictions came to pass; he married, fathered a large family, and lived a long and prosperous life, all the while excreting urine as black as ink."

In 1902, Archibald Garrod demonstrated that alkaptonuria is inherited as a single recessive Mendelian trait. He further established that homogentisic acid is a normal intermediate product in the breakdown of phenylalanine and tyrosine, and that the accumulation of homogentisic acid in alkaptonuria is caused by a block in its degradation. Garrod concluded that "the Cleavage of the benzene ring during normal metabolism results from the action of a specific enzyme, and in congenital alkaptonuria this enzyme is absent." He arrived at the Conclusion that There is a direct link between genes and enzymes, and highlighted Structure/19.html">The Importance of chemical individuality. His book, Inborn Errors of Metabolism, was the most brilliant and significant contribution to biology and medicine of its time.

Melanin is a black pigment found in the Skin and Hair. The name originates from the Greek word melan, meaning "black." This polymeric pigment is synthesized within melanosomes—granules rich in tyrosinase, a monooxygenase.