The three coenzymes biotin, tetrahydrofolate, and the vitamin B12 derivative methylcobalamin (Fig. 7) act as carriers of the single-carbon compounds CO2, bicarbonate ions, formaldehyde, and formic acid. The combining of biotin with CO2 is not a spontaneous process but depends upon adenosine triphosphate (ATP), which serves as both a phospho group carrier and the common energy currency for many cellular reactions. It can also be regarded as a coenzyme. In order to be activated by reaction with ATP, the CO2 must first combine with a hydroxide ion to form bicarbonate HCO3−. ATP then transfers a phospho group to the bicarbonate, forming the labile and short-lived carboxyl phosphate (−OOC—O—PO32−) together with adenosine diphosphate (ADP). The carboxyl phosphate, in turn, transfers the carboxyl group to the biotin prosthetic groups of the various carboxylase proteins. From them the carboxyl group is transferred onto the various sites marked by arrows in Fig. 17. An inorganic phosphate ion is released when the carboxyl group is transferred to biotin, completing a sequence that couples activation of CO2 with the cleavage of ATP to ADP and inorganic phosphate (Pi). Such coupling of ATP cleavage to biosynthesis is a common feature of much of biosynthetic metabolism.
Two other biotin-dependent reactions of great significance are the carboxylation of acetyl-CoA to malonyl- CoA and that of pyruvate to oxaloacetate (Fig. 17). The former is essential to biosynthesis of fatty acids, which are formed in a pathway which parallels (in reverse) that of β oxidation (Fig. 12). However, there are several differences. In the biosynthetic pathway, acetyl-CoA is first converted to malonyl-CoA which undergoes decarboxylation when a two-carbon unit is added to the growing fatty acid chain. This decarboxylation, together with the prior carboxylation steps, couples ATP cleavage to the biosynthesis. Furthermore, NADPH is used in the reduction steps rather than NADH or FADH2. In addition, the acyl carrier is not coenzyme A but the related prosthetic group of acyl carrier protein. Another biosynthetic process that depends upon biotin is the synthesis of glucose in the liver. Pyruvate, a product of glucose breakdown, is carboxylated to oxaloacetate which is later decarboxylated on its pathway to glucose. Again ATP cleavage is coupled to biosynthesis with the help of biotin.
Tetrahydrofolates (THF) interconvert several onecarboncompounds or fragments. As is indicated in Fig. 18, formaldehyde released from the PLP-dependent cleavage of serine is immediately trapped by THF (Fig. 14). Nitrogen N1 adds to formaldehyde to form a carboxymethyl (—CH2—COOH) derivative which can than react reversibly with loss of water to form a cyclic adduct (Fig. 18). This compound can be oxidized to the N10- methyl form. Both of these are important intermediates in a variety of biosynthetic processes. The third onecarbon carrier is vitamin B12 which can act as an acceptor, taking the methyl group from methyl-THF to form methylcobalamin (Fig. 7). This compound is transferred to the amino acid homocysteine to form methionine, one of the 20 major amino acids from which proteins are constructed. The reaction accounts for the second human requirement for vitamin B12. If the methionine dietary intake is high enough, this reaction is less important, but the enzyme is still essential for remethylation of homocysteine formed when methionine is used in a variety of processes of biological methylation.
The double ring system on which folic acid (Fig. 6) is constructed is known as pterin. In addition to the folates, a number of other pterin coenzymes are found in the human body and elsewhere in nature. Several have shorter side chains at the 6-position on the ring. Some of these compounds are used to color butterfly wings. Another, called biopterin, has a three-carbon side chain that carries two hydroxyl groups. Its reduced form, tetrahydrobiopterin, is a coenzyme for a series of hydroxylases. Among these is phenylalanine hydroxylase which is lacking in the well-known human genetic defect phenylketonuria (PKU). The reduced pterin ring has properties similar to those of FADH2. Molecular oxygen (O2) can add to form a peroxide that can donate an OH group (formally as +OH) to convert phenylalanine to tyrosine. Phenylalanine is toxic to the brain, accounting for the devastating symptoms of PKU. Another pterin derivative is molybdopterin, which has a four-carbon side chain containing two sulfur atoms and an OH group. The human body, as well as all other organisms, connects this OH group to a guanine nucleotide to give a complex cofactor somewhat resembling NAD+. The two sulfur atoms, however, bind to an atom of the metal molybdenum. The molybdenum atom is the site at which our bodies oxidize the toxic sulfite (SO32−) to the harmless sulfate (SO42−). This coenzyme, and the associated enzyme sulfite oxidase, are essential to human life. Methane-forming bacteria create a different complex side chain in methanopterin, which replaces tetrahydrofolate in those organisms. Very complex pterin derivatives form the red eye pigments of fruit flies.
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