Pathways of Amino Acid Degradation:- Several Enzyme Cofactors Play Important Roles in Amino Acid Catabolism
A variety of interesting chemical rearrangements occur in the catabolic pathways of amino acids. It is useful to begin our study of these pathways by noting the classes of reactions that recur and introducing their enzyme co factors. We have already considered one important class: transamination reactions requiring pyridoxal phosphate. Another common type of reaction in amino acid catabolism is one-carbon transfers, which usually involve one of three cofactors: biotin, tetrahydrofolate, or S-adenosylmethionine (Fig. 18–16). These cofactors transfer one-carbon groups in different oxidation states: biotin transfers carbon in its most oxidized state, CO2; tetrahydrofolate transfers one-carbon groups in intermediate oxidation states and sometimes as methyl groups; and S-adenosylmethionine transfers methyl groups, the most reduced state of carbon. The latter two cofactors are especially important in amino acid and nucleotide metabolism. Tetrahydrofolate (H4folate), synthesized in bacteria, consists of substituted pterin (6-methylpterin),
p-aminobenzoate, and glutamate moieties (Fig. 18–16). The oxidized form, folate, is a vitamin for mammals; it is converted in two steps to tetrahydrofolate by the enzyme dihydrofolate reductase. The one-carbon group undergoing transfer, in any of three oxidation states, is bonded to N-5 or N-10 or both. The most reduced form of the cofactor carries a methyl group, a more oxidized form carries a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group (Fig. 18–17). Most forms of tetrahydrofolate are interconvertible and serve as donors of one-carbon units in a variety of metabolic reactions. The primary source of one-carbon units for tetrahydrofolate is the carbon re moved in the conversion of serine to glycine, producing N5, N10-methylene tetra hydro folate. Although tetrahydrofolate can carry a methyl group at N-5, the transfer potential of this methyl group is in sufficient for most biosynthetic reactions. S-Adenosyl methionine (adoMet)is the preferred cofactor for biological methyl group transfers. It is synthesized from ATP and methionine by the action of methionine
FIGURE 18–16 Some enzyme cofactors important in one-carbon transfer reactions. The nitrogen atoms to which one-carbon groups are attached in tetrahydrofolate are shown in blue.
FIGURE 18–17 Conversions of one-carbon units on tetrahydrofolate. The different molecular species are grouped according to oxidation state, with the most reduced at the top and most oxidized at the bot tom. All species within a single shaded box are at the same oxidation state. The conversion of N5, N10-methylenetetrahydrofolate to N5 methyltetrahydrofolate is effectively irreversible. The enzymatic trans fer of formyl groups, as in purine synthesis and in the formation of formylmethionine in prokaryotes (Chapter 27), generally uses N10-formyltetrahydrofolate rather than N5-formyltetrahydrofolate. The latter species is significantly more stable and therefore a weaker donor of formyl groups. N5-formyltetrahydrofolate is a minor byproduct of the cyclohydrolase reaction, and can also form spontancously. Conversion of N5-formyltetrahydrofolate to N5, N10-methenyltetrahy drofolate, requires ATP, because of an otherwise unfavorable equilibrium. Note that N5-formiminotetrahydrofolate is derived from histidine in a pathway shown in Figure 18–26.
adenosyl transferase (Fig. 18–18, step 1). This re action is unusual in that the nucleophilic sulfur atom of methionine attacks the 5 carbon of the ribose moiety of ATP rather than one of the phosphorus atoms. Tri phosphate is released and is cleaved to Pi and PPi on the enzyme, and the PPi is cleaved by inorganic pyro phosphatase; thus, three bonds, including two bonds of high-energy phosphate groups, are broken in this reaction. The only other known reaction in which triphosphate is displaced from ATP occurs in the synthesis of coenzyme B12(see Box 17–2, Fig. 3). S-Adenosylmethionine is a potent alkylating agent by virtue of its destabilizing sulfonium ion. The methyl group is subject to attack by nucleophiles and is about 1,000 times more reactive than the methyl group of N5 methyltetrahydrofolate. Transfer of the methyl group from S-adenosylmethionine to an acceptor yields S-adenosylhomocysteine (Fig. 18–18, step 2), which is subsequently broken down to homocysteine and adenosine (step 3). Methionine is regenerated by transfer of a methyl group to homo cysteine in a reaction catalyzed by methionine synthase (step 4 ), and methionine is reconverted to S-adenosyl methionine to complete an activated-methyl cycle. One form of methionine synthase common in bacteria uses N5-methyltetrahydrofolate as a methyl donor. Another form of the enzyme present in some bacteria and mammals uses N5-methyltetrahydro folate, but the methyl group is first transferred to cobalamin, derived from coenzyme B12, to form methyl cobalamin as the methyl donor in methionine formation. This reaction and the rearrangement of L-methyl malonyl-CoA to succinyl-CoA (see Box 17–2, Fig. 1a) are the only known coenzyme B12–dependent reactions in mammals. In cases of vitamin B12 deficiency, some symptoms can be alleviated by administering not only vitamin B12 but folate. As noted above, the methyl group of methylcobalamin is derived from N5-methyltetrahy drofolate. Because the reaction converting the N5, N10 methylene form to the N5-methyl form of tetrahydrofolate is irreversible (Fig. 18–17), if coenzyme B12 is not available for the synthesis of methylcobalamin, then no acceptor is available for the methyl group of N5-methyl tetrahydrofolate and metabolic folates become trapped in the N5-methyl form. This sequestering of folates in one form may be the cause of some symptoms of the vitamin B12 deficiency disease pernicious anemia. How ever, we do not know whether this is the only effect of insufficient vitamin B12. ■ Tetrahydrobiopterin, another cofactor of amino acid catabolism, is similar to the pterin moiety of tetrahydrofolate, but it is not involved in one-carbon transfers; instead, it participates in oxidation reactions. We consider its mode of action when we discuss phenyl alanine degradation.
FIGURE 18–18 Synthesis of methionine and S-adenosylmethionine in an activated-methyl cycle. The steps are described in the text. In the methionine synthase reaction (step 4 ), the methyl group is trans ferred to cobalamin to form methylcobalamin, which in turn is the methyl donor in the formation of methionine. S-Adenosylmethionine, which has a positively charged sulfur (and is thus a sulfonium ion), is a powerful methylating agent in a number of biosynthetic reactions. The methyl group acceptor (step 2 ) is designated R.
