Catabolism of Amino Acid Carbon Skeletons
The catabolic breakdown of most of the amino acids is summarized in the Main Routes of Amino Acid Catabolism diagram in your packet. A couple of overview comments. Note the amino acids that are essential in mammals (cannot be synthesized in quantities necessary for good health). Generally these essential amino acids are those which have an irreversible reaction in the breakdown pathway.
Look at the Main Routes of Amino Acid Catabolism diagram in your packet again. Amino acids can also be categorized as being glucogenic (can be used in Gluconeogenesis) or ketogenic (cannot be used in Gluconeogenesis). Most aa's can be at least partially used in glucose synthesis. For example ilu, tyr and phe are partially glucogenic and partially ketogenic(some carbons go to acetyl-CoA, while the rest go to TCA intermediates), while leu and lys are fully ketogenic.
We will begin by looking at the catabolism of amino acids by groups: 3-C (feed into pyruvate), 4-C (feed into oxalacetate), and 5-C (feed into glutamate).
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.
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.
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:
Folate itself is composed of three components as shown on the figure.
Serine turns out to be one of the most metabolically active amino acids. It has a very high turn-over rate: it is a major source of carbons in the one-carbon pool, and it is used in the synthesis of glycine. One of the various pathways for serine synthesis from glucose is shown below:
Serine can now be used to provide a methylene group to H4-folate. (Note that Serine hydoxymethyl transferase uses PLP to catalyze a C-C bond cleavage in this reaction.)
The glycine produced in the transferase reaction can now be used to provide a second methylene group via Glycine synthase. So how many of glucose's 6 carbons can be incorporated by this pathway? (Get two serines/glucose; one carbon + glycine from each serine, then a second carbon from glycine with the remaining carbon lost as carbon dioxide. Therefore 4/6 glucose carbons can go into the one-carbon pool.)
As can be seen in the Main Folate Metabolic Pathways diagram, H4-folate can carry carbon in the various oxidation states required in a variety of metabolic reactions:
Methionine is essential for protein biosynthesis. It is also used as a source for carbons, and as a carrier for activated carbons in the one-carbon pool. In addition it serves as the source of Sulfur in cysteine biosynthesis. The latter three all involve methyl group transfers. The terminal methyl group on met is activated via reaction with ATP to give S-Adenosylmethionine, phosphate and pyrophosphate (= 2.5 ATP equiv. at a cost of 3 ATP's). This gives the high-energy sulphonium group:
S-Adenosylmethionine can now donate its activated methyl group.
We've been looking at the sources and carriers for carbon in the one-carbon pool, we can now look at some main uses for these carbons.
S-Adenosylmethionine can donate its activated methyl group. For example creatine is synthesized as shown below, starting with glycine:
Note that arginine provides "most of a urea" just as it does in the Urea Cycle, but here it is transferred to glycine instead of to water. This is a fairly active synthesis since P-creatine spontaneously and irreversibly cyclizes to creatinine, which is then excreted as waste.
© R. A. Paselk 2010;
Last modified 1 May 2013