Amino acids, degradation mechanism

B. The mechanisms of amino acid degradation are grouped according to the ways their carbon skeletons are subsequently metabolized. 

The critical feature of the Edman degradation is that it allows the N-terminal amino acid to be removed without cleaving any of the other peptide bonds. Let s see how this occurs. The mechanism of the reaction is shown in Figure 26.3. First the nucleophilic nitrogen of the N-terminal amino acid attacks the electrophilic carbon of phenyl isothiocyanate. When anhydrous HF is added in the next step, the sulfur of the thiourea acts as an intramolecular nucleophile and attacks the carbonyl carbon of the closest peptide bond. II is the intramolecular nature of this step and the formation of a five-membered ring that result in the selective cleavage of only the N-terminal amino acid. The mechanism for this part of the reaction is very similar to that for acid-catalyzed hydrolysis of an amide (see Section 19.5). However, because no water is present, only the sulfur is available to act as a nucleophile. The sulfur is ideally positioned for intramolecular attack at the carbonyl carbon of the N-terminal amino acid, so only this amide bond is broken. 

Amino acid sequence Mechanism of degradation Formulation strategy... 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

Design your own degradative pathway. You know the rules (organic mechanisms), and you ve seen the kinds of reactions that occur in the biological degradation of fats and carbohydrates inLo acetyl CoA. If you were Mother Nature, what series of steps would you use to degrade the amino acid serine into acetyl CoA ... 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Figure 6.1 Histamine synthesis and metabolism in neurons. L-histidine is transported into neurons by the L-amino acid transporter. Once inside the neuron, L-histidine is converted into histamine by the specific enzyme histidine decarboxylase. Subsequently, histamine is taken up into vesicles by the vesicular monoamine transporter and stored there until released. In the absence of a high-affinity uptake mechanism in the brain, released histamine is rapidly degraded by histamine methyltransferase, which is located postsynaptically and in glia, to telemethylhistamine, a metabolite that does not show any histamine-like activity.

Plaquet et al. (PI) found in the urine of rachitic children peptides consisting of proline, hydroxyproline, and glycine, which they believed to be the products of collagen degradation. Two similar peptides containing considerable amounts of proline and hydroxyproline were isolated from the urine of a patient with rheumatoid arthritis by Mechanic et al. (Ml). One of these peptides consisted of three proline, two hydroxyproline, and nine glutamic acid residues, the second one consisted of four proline, four hydroxyproline, and one glutamic acid residues. The N-terminal amino acid in the first peptide was demonstrated to be hydroxyproline. 

Again the close correspondence between the measured radical and carbon dioxide yields for 7-radiolysis of the N-acetyl amino acids in the solid state suggests that the mechanisms for radical production and carbon dioxide formation are closely related, as they were for the aliphatic carboxylic acids. The following mechanism has been proposed (5.) in order to account for the major degradation products and observed radical intermediates. 

A variety of peptides are utilized in the nervous system as neurotransmitters. Unlike other neurotransmitters, which can be synthesized in various parts of the neuron like the axon terminals, neuropeptides are produced by gene transcription and translation. They may colocalize and be coreleased with ACh, monoamines, or amino acid neurotransmitters. Their receptors are metabotropic and may work through a variety of effector mechanisms. Neuropeptides are formed and degraded by a variety of peptidase enzymes. 

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