Serine thymine

N -Fmoc serine benzyl ester 2, which could be prepared as shown or purchased commercially, was smoothly converted to the crystalHne O-methylthiomethyl (MTM) ether 3 in high yield via a Pummerer-Hke reaction using benzoyl peroxide and dimethyl sulfide in acetonitrile [39]. This common intermediate was used to synthesize both 5 and 8 [40]. Both Ogilvie [41] and Tsantrizos [42] had reported that I2 was an effective activator with similar MTM ether substrates. The H promoted nucleosidation reaction between O-MTM ether 3 and bis-silylated thymine 4 produced the nucleoamino acid 5 in 60% isolated yield (100% based on recovered 3). Hydrogenolytic deprotection of the benzyl ester with H2, Pd/C in MeOH gave the thymine-containing nucleoamino acid 6 in quantitative yield. 

In addition to its roles in phospholipid and sphingo-sine biosynthesis, serine provides carbons 2 and 8 of purines and the methyl group of thymine. 

Tetrahydrofolate receives one-carbon fragments from donors such as serine, glycine, and histidine and transfers them to intermediates in the synthesis of amino acids, purines, and thymine—a pyrimidine found in DNA. ... 

Fig. I. Early representation of lihoraitlease structure Legend Alanine I At.A). adenine (AN), arginine (ARG). aspartic acid (ASP), cysteine (CYS). cytosine tCN). glutamic acid (GLU), glycine (GLY). guanine IGN), liistidine (HIS), isolcucine (II.HU), leucine iLEL). lysine (LYS). methionine (MET), phenylalanine (PHH). prolinc (PRO), serine (SER), threonine (THR). thymine TN), trypiophan tTRY). ivrosine (TYR). uracil lUN). and valine (VAL)...

RNA ribonucleic acid mRNA messenger RNA rRNA ribosomal RNA scRNA small cytoplasmic RNA snRNA small nuclear RNA tRNA transfer RNA RNAse ribonuclease Ser serine T thymine Thr threonine... 

In general C-methyl groups have their origin in the primary building blocks of the molecule, but the 6-methyl in thymine (XIII) has been traced to formate, serine, and glycine (407, 408). 

The reducing property of ascorbic acid also assists another vitamin, folic acid (Figure 5.18). This is an essential co-factor in various one-carbon transfers for example the methyl group originating from the essential amino acid methionine is required in the formation of a wide variety of compounds including purines, the pyrimidine thymine, the amino acid serine, choline, carnitine, creatine, adrenalin, and many others. In its functional state, folic acid must be in its most reduced tetrahydrofolate form and this is brought about and/or maintained by ascorbic acid. 

The one-carbon groups on FH4 may be oxidized or reduced (see Fig. 40.3) and then transferred to other compounds (see Fig. 40.4 and Table 40.1). Transfers of this sort are involved in the synthesis of glycine from serine, the synthesis of the base thymine required for DNA synthesis, the purine bases required for both DNA and RNA synthesis, and the transfer of methyl groups to vitamin B12. 

The main source of C, units is the hydroxymethyl group of serine, which is transferred to THF by serine hydroxymethyltransferase (EC 2.1.2.1), forming fV -hydroxymethyl-THF (activated form dehyde). Production of C, units during histidine catabolism and in the anaerobic degradation of purines is of particular importance. C, units are incorporated during purine biosynthesis, and they provide the S-methyl group of thymine. C units are interconverted while attached to THF (Hg.2). For other metabolic sources and uses of C units, see legend to Fig.2. 

Fig. 1. Clover leaf model of a tRNA molecule (serine-specific tRNA from yeast). A = adenine. C = cytosine. G guanine. I = inosine. U = uracii. T = thymine, tj = pseudouracii.

A connection between folic acid and Bi displayed in pernicious anemia was also revealed in Shive s (1950) studies of the reversal of sulfanilamide inhibition, as mentioned earlier in the discussion of E. coli 313-3. A more direct approach to folic-Bij relations seems available in certain p-aminobenzoic acid (PAB)-deficient strains of Bacillus stearothermophilus which respond with equal sensitivities, on a molar basis, to pteroic acid and pteroylglutamic acid (Baker et al., 1956). This PAB-folic requirement is satisfied by a combination of thymine, xanthine, and cyanocobalamin. The concentration of cyanocobalamin required under these conditions was high (10 ug. %) as contrasted with the requirement (0.01 ug-%) of a Bi2-requiring strain of B. stearothermophilus. The cobalamin supplement for the PAB-deficient strain was not replaceable by methionine on the other hand, cyanocobalamin for the B 12 deficient strain ivas replaceable by methionine. XTnexpectedly, cyanocobalamin did not reverse inhibition by sulfanilamide of the PAB-deficient strain in the presence of methionine, xanthine, thymine, glycine, serine, threonine, and leucine—the combination found effective by Shive in reversing sulfanilamide inhibition of wild-type E. coli. 

Pantothenate or thiamine, combined with methionine, purine, Bij, serine, and thymine, helped reverse the toxicity of sulfanilamide for E. colt (Shive, 1950). More intimations of a connection to Ci metabolism soon came forth (a) a mutant of Saccharomycea cerevisiae required pantothenate, methionine, adenine, and histidine to replace PABA (Pomper, 1952) (b) the interchangeability of PABA and pantothenate for Bacterium linens (Purko et al., 1954) (c) serine stimulated the production of pantothenatp from valine plus /S-alanine (Altenbem and Ginoza, 1954) and (d) reduced CoA was needed in cell-free Ci-transfer systems in which PGA or FH was supplied instead of FH4 or FH4-derivatives (Wright, 1958) The ate has been located an enzyme from E. coli catalyzes the reaction VIII (McIntosh et al., 1957). 

An interesting approach to obtain peptides in which the purine or pyrimidine residues were correctiy spaced for interaction with the nucleic acids, was made by using a spacer amino acid [49]. Serine was used as a spacer and several protected tetrapeptides, e.g., a-N-t-BOC-L-seryl-D,L-P-(thymin-l-yl)ala-nyl-L-seryl-D,L-P-(thymin-l-yl)alanine, ethyl ester, were synthesized but little was reported about their solution properties and interactions with the nucleic acids. The polymerization of the nucleic acid base-substituted L-lysine derivatives by N-carboxyamino acid anhydride method was also reported [52, 53]. 

More recently it has been observed that 2-amino-4-hydroxy-6,7-dimethyltetra-hydropteridine, which lacks N °, is unable to substitute for FH as a coenzyme in the utilization of formaldehyde for the enzymic formation of serine and of thymine-methyl (48a). The corresponding dimethyldihydropteridine can serve as a substrate for dihydrofolic acid reductase. 

The (9-carbon of serine as well as the a-carbon of glycine were extensively incorporated into the methyl group of thymine in the adult rat (334). In addition, formate-C served as a precursor of the methyl group of thymine both in vivo (29) and in vitro (335) formaldehyde was also utilized for thymine methyl group synthesis (336). Isotopic data indicated that the hydroxymethyl group of serine, doubly labeled with and D, was transferred to position 5 of thymine with a minimum of 1.5 atoms of D per carbon atom this demonstrated that the /3-carbon of serine was not metabolized all the way to formate (337),... 

A particularly active field of biochemical research deals with the manner in which folic add functHms in intomediary metabolism as a corollary of such studies has come knowledge of the conversion of foUc add to its functional forms. It was recognized eariy that folic acid must be concerned in some manner with the biosynthesis of purine bases and thymine. Later it was also shown to be involved in the formation of methionine, serine, and histidine. Subsequently it was learned that folic acid was the carrier of a single-carbon unit needed at a point in the synthesis of these metabo-... 

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