Amino acid acetoacetate from

Metabolic acidosis with an increased SAG commonly results from increased endogenous organic acid production. In lactic acidosis, lactic acid accumulates as a by-product of anaerobic metabolism. Accumulation of the ketoacids /S-hydroxybutyric acid and acetoacetic acid defines the ketoacidosis of uncontrolled diabetes mellitus, alcohol intoxication, and starvation (see Table 51-5). In advanced renal failure, ac-cumulation of phosphate, sulfate, and organic anions is responsible for the increased SAG, which is usually less than 24 mEq/L." The severe metabolic acidosis seen in myoglobinuric acute renal failure caused by rhabdomyolysis may be caused by the metabolism of large amounts of sulfur-containing amino acids released from myoglobin. 

The pathways involved in the catabolism of the individual amino acids range from one-step reactions, such as with aspartate, glutamate, and alanine, which use the appropriate amino transferases, to multistep pathways of the aromatic amino acids and lysine (e.g., tyrosine is degraded in four steps to acetoacetate and fumarate). 

B. The liver is again the major organ that synthesizes the principal long-term fuel, ketone bodies, acetoacetate, and 3-hydroxybutyrate, which are made from both amino acids and fatty acids. 

In mammals, muscle breakdown or excess protein intake results in an imbalance between the fates of the carbon chains and the amino nitrogen. Unlike fat (lipid storage) or glycogen (carbohydrate storage), excess amino acids are not stored in polymeric form for later utilization. The carbon chains of amino acids are generally metabolized into tricarboxylic acid (TCA) cycle intermediates, although it is also possible to make ketone bodies such as acetoacetate from some. Conversion to TCA intermediates is easy to see in some instances. For example, alanine is directly transaminated to pyruvate. 

The procedure is convenient for the synthesis of a-amino acids from mono- or di-substituted acetoacetic esters (80-98%). ... 

How does the liver meet its ovm energy needs a-Ketoacids derived from the degradation of amino acids are the liver s own fuel. In fact, the main role of glycolysis in the liver is to form building blocks for biosyntheses. Furthermore, the liver cannot use acetoacetate as a fuel, because it has little of the transferase needed for acetoacetate s activation to acetyl CoA. Thus, the liver eschews the fuels that it exports to muscle and the brain. 

The reaction with ethyl acetoacetate is exceptional, a condensation product of amino-acid (1 mol.) with acetone (1 mol.) resulting. This product cannot be obtained directly from acetone. 

Catabolism of tyrosine and tryptophan begins with oxygen-requiring steps. The tyrosine catabolic pathway, shown at the end of this chapter, results in the formation of fumaric acid and acetoacetic acid. Tryptophan catabolism commences with the reaction catalyzed by tryptophan-2,3-dioxygenase. This enzyme catalyzes conversion of the amino acid to N-formyl-kynurenine. The enzyme requires iron and copper and thus is a metalloenzyme. The final products of the pathway are acetoacetyl-CoA, acetyl-CoA, formic acid, four molecules of carbon dioxide, and two ammonium ions. One of the intermediates of tryptophan catabolism, a-amino-P-carboxymuconic-8-semialdehyde, can be diverted from complete oxidation, and used for the synthesis of NAD (see Niacin in Chapter 9). 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

Succinyl-CoA can also be synthesized from propionyl-CoA by way of methylmalonyl-CoA, which is formed in the oxidation of branched-chain amino acids (e.g., valine, isoleucine) and in the terminal stage of oxidation of odd-chain-length fatty acids (Chapter 18). Succinyl-CoA is utilized in the activation of acetoacetate (Chapter 18) and the formation of (5-aminolevulinate, a precursor of pro-phyrin (Chapter 29). 

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