|Lecture Notes: 13 February||
Ser and ala are converted in single step processes to pyruvate. Cys is converted after first oxidizing and removing sulfur as sulfate. (Threonine, glycine and part of tryptophan can also breakdown to pyruvate, but we will look at other paths.)
Asn is hydrolyzed in one step to aspartate, which in turn is transaminated in one step to oxalacetate. Threonine feeds into the TCA cycle through succinyl-CoA instead of oxalacetate. Thr is first deaminated via a dehydratase as seen earlier, then decarboxylated by Pyruvate DH Complex to give propionyl-CoA, which is then transformed via a series of steps to give succinyl-CoA., as discussed below.
Propionyl-CoA metabolism: propionyl-CoA is an intermediate in the catabolism of a number of amino acids, as well as in the breakdown of odd-chain fatty acids. Propionyl-CoA (3-C) enters the TCA Cycle at succinyl-CoA (4-C), thus another carbon must be added to bring it into mainstream metabolism. A biotin-dependent carboxylase adds carbon dioxide at the cost of one ATP to give D-methylmalonyl-CoA. D-methylmalonyl-CoA is then racemized to L-methylmalonyl-CoA. Methylmalonyl-CoA is a branched-chain, whereas succinyl-CoA is straight-chain: the carboxyl group and a hydrogen must be exchanged. This exchange requires C-C bond-breaking and making, a process apparently involving a Co-C bond intermediate. The cobalamin cofactor derived from Vit B12 is used in catalyzing this reaction.
Five aa's feed into glutamate which in turns feeds into the TCA cycle at 2-oxo-glutarate.
valine (val), leucine (leu), and isoleucine (ilu). The metabolism of each of these three amino acids begins with the same theme: transaminase; DH Complex; beta-oxidation. Due to the irreversible nature of the DH Complex all three are essential.
Lysine: Note the unusual "transamination" of the epsilon amino group where lysine is first reduced using NADPH and condensed with 2-oxo-glutarate to give L-saccharopine. Saccharopine is then split and oxidized using NAD+ to give glutamate and "lysine aldehyde." The aldehyde is then oxidized again and the resulting 2-aminoadipate now follows the branched chain pattern: transaminase, DH Complex, beta-oxidation.
The last two amino acids on the diagram are broken into two parts: half feeds into the TCA cycle at fumerate (glucogenic), and the other half goes to acetoacetate (ketogenic). Phe is first hydroxylated using molecular oxygen and the cofactor tetrahydrobiopteran to give tyr. Tyrosine is thus only an essential aa if insufficient phe is present in the diet to synthesize it. Tyr is next transaminated followed by a couple of oxidations of the benzene ring using molecular oxygen and involving iron as a cofactor. These reactions open the ring, which is then hydrolyzed to give fumerate and acetoacetate.
The one-carbon pool consists of a number of sources and sinks for single carbon transfers involved in biosynthesis. It involves the catabolism of two additional amino acids, met and gly, and the biosynthesis of ser and gly.
The main sources of carbon for the pool are:
Tetrahydrofolate is the major carrier involved in single carbon transfers. Tetrahydrofolate is made from the vitamin folate by reducing the 5, 6, 7, and 8 positions of the pteridine ring with two sequential DH reactions using NADPH:
The major carriers of "activated" carbon in the pool are:
Last modified 13 February 2009