Proteins are broken down by a variety of proteases that hydrolyze the peptide bonds to generate smaller peptides and amino acids. Those amino acids that are not used for building new proteins may be broken down further to enter the metabolic processes discussed in this chapter.
There is a large variety of proteases, classified into one of six groups (as of 2008): serine proteases, metalloproteases, aspartic acid proteases, cysteine proteases, threonine proteases, and glutamic acid proteases. All of them work by forming a nucleophile at their active site to attack the peptide carbonyl group. They differ in the construction of their active sites, and the specificity of the target sequences to be cleaved. The MEROPS database (http:// merops.sanger.ac.uk/) lists hundreds of enzymes and their specific recognition sites. As with other enzymes, recognition is based on formation of stabilizing hydrogen bonds between enzyme and target. In the case of proteases, many of the important stabilizing bonds must be formed right around the cleavage site, thus leading to specific recognition sequences.
Although cleavage is often thought of as a way of destroying the activity of a protein, in fact, specific cleavage of inhibitory parts of a protein can activate it. A prominent example of this (the caspase cascade) is discussed in the apoptosis section of the cell cycle chapter.
Some proteases are secreted and do their work extracellularly. These include digestive enzymes such as pepsin, trypsin, and chymotrypsin, as well as bloodstream proteases like thrombin and plasmin that help control clotting. The immune system also uses proteases to destroy invading cells and viruses.
In their conversion to metabolic intermediates, the amino acids first undergo deamination. The primary goal of deamination is to excrete excess nitrogen (as urea) and then use or convert (to glucose) the remaining carbon skeleton. This deamination is a two-part process: the first step to deamination is usually a transamination catalyzed by an aminotransferase, in which the amino group of the amino acid is transferred to α-ketoglutarate which then yields a new α-keto acid of the amino acid and glutamate.
The amino group of glutamate could then transferred to oxaloacetate to form α-keto-glutarate and aspartate. That series of transaminations transforms the original amino acid, but does not get rid of the amino group nitrogen. The alternative pathway is deamination of the glutamate by glutamate dehydrogenase, which generates α-ketoglutarate and ammonia, using either NAD+ or NADP as the oxidizing agent.
The amino acids break down into one of the following seven metabolic intermediates: pyruvate, acetyl-CoA, acetoacetate, a-ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate as follows: 1) Ala, Cys, Gly, Ser, Thr, Trp break down to pyruvate; 2) Ile, Leu, Lys, Thr to acetyl-CoA; 3) Leu, Lys, Phe, Trp, Tyr to acetoacetate; 4) Arg, Glu, Gln, His, Pro to α-ketoglutarate; 5) Ile, Met, Val to succinyl-CoA; 6) Asp, Phe, Tyr to fumarate; 7) Asn, Asp to oxaloacetate.