Pyruvate, removal

The pyruvate dehydrogenase complex (PDC) is a noncovalent assembly of three different enzymes operating in concert to catalyze successive steps in the conversion of pyruvate to acetyl-CoA. The active sites of ail three enzymes are not far removed from one another, and the product of the first enzyme is passed directly to the second enzyme and so on, without diffusion of substrates and products through the solution. The overall reaction (see A Deeper Look Reaction Mechanism of the Pyruvate Dehydrogenase Complex ) involves a total of five coenzymes thiamine pyrophosphate, coenzyme A, lipoic acid, NAD+, and FAD. 

Catalytic reduction of the nitrile 79 in the presence of semicarbazide affords initially the semicarbazone of 80. Hydrolysis-interchange, for example in the presence of pyruvic acid, gives the aldehyde 80. Condensation with the half ester of malonic acid leads to the acrylic ester 81 the double bond is then removed by means of catalytic reduction (82). Base catalyzed reaction of the... 

Transamination is the most common initial reaction of amino acid catabohsm. Subsequent reactions remove any additional nitrogen and restmcmre the hydrocarbon skeleton for conversion to oxaloacetate, a-ketoglutarate, pyruvate, and acetyl-CoA. 

These enzymes catalyse the non-hydrolytic cleavage of bonds in a substrate to remove specific functional groups. Examples include decarboxylases, which remove carboxylic acid groups as carbon dioxide, dehydrases, which remove water, and aldolases. The decarboxylation of pyruvic acid (10.60) to form acetaldehyde (10.61) takes place in the presence of pyruvic decarboxylase (Scheme 10.13), which requires the presence of thiamine pyrophosphate and magnesium ions for activity. 

The alanine cycle accomplishes the same thing as the Cori cycle, except with an add-on feature (Fig. 17-11). Under conditions under which muscle is degrading protein (fasting, starvation, exhaustion), muscle must get rid of excess carbon waste (lactate and pyruvate) but also nitrogen waste from the metabolism of amino acids. Muscle (and other tissues) removes amino groups from amino acids by transamination with a 2-keto acid such as pyruvate (oxaloacetate is the other common 2-keto acid). 

Control of pymvate dehydrogenase activity is via covalent modification a specific kinase causes inactivation of the PDH by phosphorylation of three serine residues located in the pyruvate decarboxylase/dehydrogenase component whilst a phosphatase activates PDH by removing the phosphates. The kinase and phosphatase enzymes are non-covalently associated with the transacetylase unit of the complex. Here again we have an example of simultaneous but opposite control of enzyme activity, that is, reciprocal regulation. 

A major aim of amino acid catabolism is removal of the a-NH2 group, which results in the formation of ammonia which is then converted to urea. The removal of the a-NH2 group for most amino acids results in the formation of a carbon-compound, which is usually an oxoacid (e.g. the oxoacid for alanine is pyruvate). 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

The whole process is multi-step, and catalysed by the pyruvate dehydrogenase enzyme complex, which has three separate enzyme activities. Dnring the transformation, an acetyl group is effectively removed from pyruvate, and passed via carriers thiamine... 

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