Diketopiperazine Formation During Investigations of Amino Acid Racemization in Dipeptides

Steinberg, Spencer M.; Bada, Jeffrey L.

doi:10.1126/science.213.4507.544

Cited by 93 publications

(71 citation statements)

References 7 publications

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“…6 The Power of Enzymes as Catalysts Wolfenden and Snider the half-time for hydrolysis of a single peptide bond. 14,15 That may explain the fact that proteins in higher organisms, which must survive for days or weeks, are usually N-acetylated, whereas N-acetylation is seldom observed in proteins from microorganisms with short generation times. 14 Next, we considered the hydrolysis of the internucleotide linkages in nucleic acids.…”

Section: Degrees Of Difficulty Of Biological Reactions In Watermentioning

confidence: 99%

The Depth of Chemical Time and the Power of Enzymes as Catalysts

2001

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The fastest known reactions include reactions catalyzed by enzymes, but the rate enhancements that enzymes produce had not been fully appreciated until recently. In the absence of enzymes, these same reactions are among the slowest that have ever been measured, some with half-times approaching the age of the Earth. This difference provides a measure of the proficiencies of enzymes as catalysts and their relative susceptibilities to inhibition by transition-state analogue inhibitors. Thermodynamic comparisons between spontaneous and enzyme-catalyzed reactions, coupled with structural information, suggest that in addition to electrostatic and H-bonding interactions, the liberation of water molecules from an enzyme's active site into bulk solvent sometimes plays a prominent role in determining the relative binding affinities of the altered substrate in the ground state and transition state. These comparisons also indicate a high level of synergism in the action of binding determinants of both the substrate and the enzyme, that are not directly involved in the chemical transformation of the substrate but contribute to the rate of its transformation at an enzyme's active site.

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Section: Degrees Of Difficulty Of Biological Reactions In Watermentioning

confidence: 99%

The Depth of Chemical Time and the Power of Enzymes as Catalysts

2001

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“…showed that linear peptides containing isoleucine residue cyclizedto 2,5-diketopiperazines 21 . Cyclic dipeptides have been suggested as easily formed peptides in the chemical evolutionary process 22 and important compounds in the development of homochirality 23 , because of theireasy formation from amino acids and the difference between diastereomers in hydrophobicity.The topic of this research is the simple chiral cyclic dipeptides (cyclo-(alanyl-alanine): Homo-L-CP (1) and Hetero-CP (2)) shown in Figure 1.In particular, the epimerization and ring-opening reactions are investigated in basic aqueous solutions.The epimerization of Homo-L-CP (1) and (3) will proceed at first from the hydrogen abstraction step to give solvated anion intermediates (4) and (5) 15 .…”

Section: Oriental Journal Of Chemistrymentioning

confidence: 99%

Epimerization of Cyclic Alanyl-Alanine in Basic Solutions

Munegumia¹,

Fujimoto²,

MichioTakada³

et al. 2014

Orient. J. Chem

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Alanine anhydrides (Cyclo-(Ala-Ala)) are the simplest dipeptides that have two chiral centers and three diastereomers: Cyclo-(L-Ala-L-Ala), Cyclo-(D-Ala-D-Ala), and Cyclo-(L-Ala-D-Ala).Analysis of the epimerization of these peptides may throw light on the development of homochirality in proteins. We show that the epimerization rate of Cyclo-(L-Ala-L-Ala) and Cyclo-(D-Ala-D-Ala) is higher than that of Cyclo-(L-Ala-D-Ala), while the ring-opening rates of Cyclo-(L-Ala-L-Ala) and Cyclo-(D-Ala-DAla) arelower than that of Cyclo-(L-Ala-D-Ala) in basic aqueous solutions. The total reaction resulted in the preferred stability of Cyclo-(L-Ala-L-Ala) and Cyclo-(D-Ala-D-Ala) to Cyclo-(D-Ala-L-Ala).

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“…Amino acid residues in diketopiperazines have been found to undergo rapid racemization at both neutral and basic pH values (7)(8)(9)(10)(11). Racemization in aspartame solutions heated at neutral pH should thus take place primarily in the diketopiperazine decomposition product.…”

Section: Discussionmentioning

confidence: 99%

“…We were particularly interested in the diketopiperazine pathway since results obtained in this laboratory (7) and in earlier work (8)(9)(10) had demonstrated that amino acid residues in diketopiperazines are highly susceptible to racemization at both neutral and basic pH values. Since the presence of D amino acids in the human diet may have a variety of consequences, many of which are only poorly understood (11)(12)(13), it would be important to establish the rate of racemization of aspartic acid and phenylalanine in aspartame and its diketopiperazine decomposition product.…”

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Racemization of aspartic acid and phenylalanine in the sweetener aspartame at 100 degrees C.

Boehm¹,

Bada²

1984

Proc. Natl. Acad. Sci. U.S.A.

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The racemization half-lives (i.e., the time required to reach a D/L = 0.33) at pH 6.8 for aspartic acid and phenylalanine in the sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester) were determined to be 13 and 23 hours, respectively, at 100'C. Racemization at this pH does not occur in aspartame but rather in its diketopiperazine decomposition product. Our results indicate that the use of aspartame to sweeten neutral pH foods and beverages that are then heated at elevated temperature could generate D-aspartic acid and Dphenylalanine. The nutritive consequences of these D-amino acids in the human diet are not well established, and thus aspartame should probably not be used as a sweetener when the exposure of neutral pH foods and beverages to elevated temperatures is required. At pH 4, a typical pH of most foods and beverages that might be sweetened with aspartame, the half-lives are 47 hours for aspartic acid and 1200 hours for phenylalanine at 100'C. Racemization at pH 4 takes place in aspartame itself. Although the racemization rates at pH 4 are slow and no appreciable racemization of aspartic acid and phenylalanine should occur during the normal use of aspartame, some food and beverage components could conceivably act as catalysts. Additional studies are required to evaluate whether the use of aspartame as a sugar substitute might not in turn result in an increased human consumption of D-aspartic acid and D-phenylalanine.A reduction in human sugar consumption is advocated for numerous reasons, with the prevention of dental caries and obesity probably being the most compelling. However, efforts to find a sugar substitute have not been generally successful. Recently, a new sweetener, aspartame, the methyl ester of the dipeptide L-aspartyl-L-phenylalanine, has been approved by the Food and Drug Administration as a sugar substitute in certain foods and beverages. Aspartame has a sweetness factor nearly 200 times that of sucrose (1, 2). Moreover, since aspartame is composed of amino acids it is classified as a "natural" sweetener in contrast to saccharin, which is considered artificial (1). Whether aspartame is a safe alternative to sugar in the human diet, however, remains controversial (3, 4). Several potential problems exist. For example, some individuals (phenylketonurics) are highly susceptible to excess phenylalanine in their diet and thus are cautioned on the package of the commercially available product about using aspartame.In aqueous solution, aspartame decomposes (1, 5, 6) via a series of reactions that include ester and peptide-bond hydrolysis and cyclization to the diketopiperazine, 3-carboxymethyl-6-benzyl-2,5-piperazinedione. We were particularly interested in the diketopiperazine pathway since results obtained in this laboratory (7) and in earlier work (8-10) had demonstrated that amino acid residues in diketopiperazines are highly susceptible to racemization at both neutral and basic pH values. Since the presence of D amino acids in the human diet may have a variety of consequences...

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Diketopiperazine Formation During Investigations of Amino Acid Racemization in Dipeptides

Cited by 93 publications

References 7 publications

The Depth of Chemical Time and the Power of Enzymes as Catalysts

The Depth of Chemical Time and the Power of Enzymes as Catalysts

Epimerization of Cyclic Alanyl-Alanine in Basic Solutions

Racemization of aspartic acid and phenylalanine in the sweetener aspartame at 100 degrees C.

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