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E-N-Hydroxylysine'9 and 5-N-Hydroxyornithine,20 21 and Hydroxylamine Derivatives of Amino Acids, Cyclserine,22, 23 Have Been Reported in Recent Years

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E-N-Hydroxylysine'9 and 5-N-Hydroxyornithine,20 21 and Hydroxylamine Derivatives of Amino Acids, Cyclserine,22, 23 Have Been Reported in Recent Years VOL. 50, 1963 CHEMISTRY: T. VISWANATHA 967 4 Cf. Magee, J. L., ref. 1, p. 142. 5 In special cases, there may occur instants of time at which all but one of the ak'S are zero. Those instants constitute a set of zero measure on the time axis. 6Ref. 1, p. 331. 7Heisenberg, W., The Physical Principles of the Quantum Theory (New York: Dover Publica- tions reprint), p. 44. 8 The uncertainty of the phase change, 5v, and Ap are correlated in the sense that 6p > 27r if Ap > 8p, as was shown by Heisenberg, ref. 7, p. 45. 9 Davydov, A. S., Theory of Molecular Excitons (New York: McGraw-Hill, 1962). 10 These excitons are still propagating waves and are "... not localized in the full sense of the word." Ref. 9, p. 68. 1' Merzbacher, E., Quantum Mechanics (New York: John Wiley and Sons, 1961), p. 470. 12 Forster, Th., Ann. Phys., 2, 55 (1948). 13 McCrea, W. H., and F. J. W. Whipple, Proc. Roy. Soc. Edinburgh, A60, 281 (1940). 14 Bay, Z., and R. M. Pearlstein, these PROCEEDINGS, in press. 15 Complete incoherence can only be achieved with infinitely high collision rates, which would lead to infinitely broad spectra. STUDIES ON CYCLOSERINE-CATALYZED REACTIONS BY T. VISWANATHA DEPARTMENT OF CHEMISTRY AND INSTITUTE OF MOLECULAR BIOLOGY, UNIVERSITY OF OREGON, EUGENE Communicated by V. Boekelheide, August 12, 1963 The reaction of diisopropylphosphofluoridate (DFP) with chymotrypsin and other serine esterases has been well documented in literature'-4 and the sequence of amino acids of the peptides containing the diisopropyl phosphoryl (DIP) moiety from various DFP-inhibited serine esterases has been established.6-'0 The phosphoryl moiety appears to be located on a serine residue in the enzyme protein. Also, the specific acetylation of chymotrypsin with p-nitrophenyl acetate originally reported by Balls and Aldrich" has been shown to result in the acetylation of the serine hydroxyl group which presumably is the same serine residue as that involved in the phosphorylation with DFP.12 Several mechanisms have been proposed to ex- plain the catalytic action of chymotrypsin and other esterases susceptible to inhibi- tion by DFP.'3-'6 However, none of the model systems proposed, e.g. the oxazo- line model' and the bicyclic intermediate formed from aspartyl serine peptide,'6 was either catalytic or able to react with DFP. During an investigation on the second phosphorylation site in DIP-trypsin,'7 a new amino acid was observed and on the basis of its chromatographic and electro- phoretic behavior and its susceptibility to periodate oxidation, it was tentatively concluded to be hydroxylysine.'8 However, in the course of the isolation of this new amino acid on a large scale, it was found to differ from 5-hydroxylysine in its chemical properties despite its striking resemblance to the latter on the basis of criteria earlier employed. Some propertiesisa of this new amino acid suggested that it could be a derivative of hydroxylamine. Several hydroxylamino acids, e-N-hydroxylysine'9 and 5-N-hydroxyornithine,20 21 and hydroxylamine derivatives of amino acids, cyclserine,22, 23 have been reported in recent years. A study of the properties of some of these hydroxylamino acids was undertaken with the idea of Downloaded by guest on September 25, 2021 968 CHEMIISTRY: T. VISWANATHA PROC. N. A. S. SW00 A~~~~~~~~d4 -oo 'Q += Go 00 cd , rn-? 0~~~~~~~~~~~~~~~~~~~~ X o ko 4-D~ 4 Downloaded by guest on September 25, 2021 VOL. 50, 1963 CHEMISTRY: T. VISWANATHA 969 obtaining information potentially pertinent to the isolation and characterization of the unknown amino acid observed in trypsin and chymotrypsin. This paper deals with the catalytic properties of one such hydroxylamino acid, cycloserine.22 The studies reported herein were prompted by the observation that cycloserine could catalyze the hydrolyses of DFP (which is also catalyzed by imidazole and hydroxylamine) and of p-nitrophenyl diethyl phosphate (E600) (hydroxylamine being the only other known model compound that can function in a similar manner with this latter compound). Materials.-Cycloserine was prepared from L-serine methyl ester according to the procedure described.24 The material crystallized in the form of rosettes and was found to have two titrable groups, one with a pK of 4.10 and another with a pK of 7.10-7.20. Its purity was further estab- lished by the absence of serine or other amino acids. One of the preparations of cycloserine was carried out under more alkaline conditions than normally employed.24 The high alkaline pH led to dimerization23 of cycloserine to the diketopiperazine form, and the product isolated was a mixture of cycloserine and its diketopiperazine. This preparation was characterized by its rela- tively low solubility in water as compared to cycloserine and by the absence of stoichiometry between the group with pK 4.10 and that with a pK of 7.10. Titration studies suggested that about 75% of the material in the above-mentioned preparation was in the diketopiperazine form. DFP was obtained from Aldrich Chemical Company, Milwaukee, Wisconsin. Cinnamoyl imidazole (CI) was obtained from Dr. S. A. Bernhard. Carboxypeptidase-A, subjected to treat- ment with DFP, was purchased from Worthington Biochemicals, Freehold, N.J. Experimental.-Four hundred mg of cycloserine in 9 ml of water were treated with 400 mg of pure DFP in 1 ml of isopropanol. This solution, originally at pH 3.8, was brought to pH 6.80 by the addition of 0.5 N KOH and maintained at that pH with the aid of an automatic titrator.'5 The reaction was accompanied by the consumption of alkali. At the end of 10 hr, when the alkali consumption had considerably slowed down, the solution was adjusted to pH 6.0 and evaporated to dryness under reduced pressure. The residue was dissolved in water and desalted by passing over Dowex 50 (H+) column, and the material eluted with dilute NH40H. The ammonium hydroxide eluate was taken to dryness, and the residue was dissolved in 15 ml of redistilled, con- stant boiling HCl and subjected to partial hydrolysis in a sealed tube for 90 min at 105°C. The hydrolysate was evaporated to dryness under reduced pressure, and traces of HC1 were removed by repeated additions of water followed by evaporation to dryness. The hydrolyzed residue was made up to 50 ml with water. A small sample was analyzed for amino acids by the procedure of Spackman, Stein, and Moore26 with the aid of a Beckman-Spinco model amino acid analyzer (results in Fig. 1). The chromatogram showed the presence of an acidic amino acid, serine, and another component emerging at 370 ml of effluent volume of the buffer. The DFP-treated cycloserine (following incubation at pH 6.8) was also analyzed for any free amino acids that might be present by means of the amino acid analyzer. As with cycloserine, no ninhydrin-reacting component was observed when such analyses were made either on the long 150-cm column for acidic and neutral amino acids or on the short 15-cm column used for the deter- mination of basic amino acids. However, exposure of the DFP-treated cycloserine to alkaline pH (9.5) for 10 min and subsequent analyses resulted in the formation of a ninhydrin-positive TABLE 1 component that emerges at 29 ml of the effluent TA E 1 volume on the 15-cm short column. The nature PHOSPHOSERINE OBTAINED FROM THE of this amino acid has not been identified. PARTIAL ACID DIGEST OF DFP-TREATED Results.-The acidic component present CYCLOSERINE in the hydrolysate was isolated by a col- hydrolysisTime of Phosphoserine Serine umn chromatographic technique similar No. (hr) (moles) (,umoles) to the one used in the analytical procedure 2 2 1. 39* 0.47 mentioned above and was desalted. It 3 10 0.032 1.14 was identified as o-phosphoserine by its 4 12 0.032 0.96 * analysis revealed 2 of in mobility on the amino acid analyzer col- organicPhosphatephosphate in the H2S04 digest of thsolesthe sample, Downloaded by guest on September 25, 2021 970 CHEMISTRY: T. VISWANATHA PROC. N. A. S. TABLE 2 umn, by its conversion to serine on pro- THE FIRST-ORDER RATE CONSTANTS OF CI longed acid hydrolysis, and by the de- HYDROLYSIS IN THE PRESENCE OF CYCLO- 27 SERINE termination of its phosphorus content. ,-First-Order Rate Constants (moles/sec.)*-_ The results obtained in these studies are diketopiperazineCycloserine-Neryshown in Table 1. Nearly 200 1molesmos of pH* Cycloserinet mixturew 4.35 3.0 X 10-3 o-phosphoserine were isolated in the ex- 4.85 2.59 X 10-3 periment described above. 5.30 1.87 X 10-3 (2760)§ 1.67 X 10-3 Treatment of the above-mentioned 5.98 2.86 X 10-3 (2770) 1.06 X 10-3 6.86 1.8 X 10-3 (2810) 7.8 X 10-4 cycloserine-diketopiperazine mixture with 7.85 1.2 X 10-3 (2750) DFP followed by analyses of the partial 8.90 2.4 X 10-4 (2730) ' 9.18 7.1 X 10-4 hydrolysate under conditions identical to * All values reported here were obtained after cor- those used earlier, showed several acidic rection for the spontaneous hydrolysis of CI i 0.025 M acetate buffer between pH 4.35 andinhyd.iti5.30;nihdn-otvecm nnsinaiini dditi 0.025 M phosphate buffer between pH 6.0 and 8.0; and 0.025 M pyrophosphate buffer at pH 9.0. to o-phosphoserine (Fig. 2). Exposure of t Cycloserine concentration 1.67 X 10-3 M; C1I this acid to the action concentration 2 X 10 M in a final volume of 3.0 ml.
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