The use of intravenous dipeptides shows great promise as an avenue for the provision of amino acids that may otherwise be difficult to deliver via nutrient infusions. The physical/chemical properties and metabolism of numerous dipeptides have now been explored in experimental and human studies. It has been found that these agents have the capacity to spare nitrogen and support serum protein levels in a fashion equivalent to that of intravenous free amino acids. An additional benefit is the ability to deliver certain amino acids that are relatively unstable or poorly soluble in aqueous solutions. These various aspects of intravenous dipeptides are considered in this review.
Get full access to this article
View all access options for this article.
References
1.
Meister A.Biochemistry of amino acids. Vol 1. New York: Academic Press, 1965:1-57.
2.
Thierfelder H., Von Cramm E.Uber glutaminhältige Polypeptide und zur Frage ihres Vorkommens in Eiwess. Z Physiol Chem1919;105:58-62.
3.
Stehle P., Pfaender P., Fürst P.Isotachophoretic analysis of a synthetic dipeptide L-alanyl-L-glutamine. Evidence for stability during heat sterilization. J Chromatogr1984;294:507-12.
4.
Daabees TA, Stegink LDL-Alanyl-L-tyrosine as a tyrosine source during intravenous nutrition of the rat. J Nutr1978;108:1104-13.
5.
Steinberg S. , Bada JLDiketopiperazine formation during investigation of amino acid racemization in dipeptides. Science1981;213:544-5.
6.
Luo S., Liao CX, McClelland JF, et al. Formation of acyclide imide in aspartyl or asparaginyl glycyl peptides induced by heating in the dry state. Int J Pept1987;29:728-33.
7.
Mazur RHAspartame-a sweet surprise. J Toxicol Environ Health1976;2:243-9.
8.
Homler BEAspartame: implications for the food scientist. In: Stegink LD, Filer LJ , eds. Aspartame physiology and biochemistry. New York: Marcel Dekker, 1984:247-62.
9.
Boehm MF, Bada JLRacemization of aspartic acid and phenylalanine in the sweetener aspartame at 100°C. Proc Natl Acad Sci USA1984;81:5263-6.
10.
Smith GG, Silva De Sol B.Racemization of amino acids in dipeptides shows COOH > NH2 for non-sterically hindered residues. Science1979;207:765-7.
11.
Kriausakul N., Mitterer RMIsoleucine epimerization in peptides and proteins: kinetic factors and application to fossils proteins. Science1978;201:1011-4.
12.
Veber DF, Gund P.On the ease of base-catalyzed epimerization ofN-methylated peptides and diketopiperazines . J Am Chem Soc1979;101:1885-7.
13.
Hilton CW, Prasad C., Vo P., et al. Food contains the bioactive peptide, Cycle(His-Pro). J Clin Endocrinol Metab1992;75:375-8.
14.
Gallo-Torres H., Heimer EP, Witt C., et al. The in vivo gastrointestinal absorption in rats of the intact cyclo(L-leucylglycine) dipeptide . Can J Physiol Pharmacol1984;62:319-28.
15.
Hoffman PL, Walter R., Bulat M.An enzymatically stable peptide with activity in the central nervous system: its penetration through the blood brain barrier. Brain Res1977;122:87-94.
16.
Stehle P., Kuhne B., Kubin W., et al. Synthesis and characterization of tyrosine- and glutamine-containing peptides. J Appl Biochem1982;4:280-6.
17.
Stehle P., Fürst P.Isotachophoretic control of peptide synthesis and purification. A novel approach using ultraviolet detection at 206 nm. J Chromatogr1985;346:271-9.
18.
Monter B., Herzog B., Stehle P., et al. Kinetically controlled synthesis of dipeptides using ficin as biocatalyst. Biotec Appl Biochem1991;14:183-91.
19.
Adibi SA, Krzysik BA, Drash ALMetabolism of intravenously administered dipeptides in rats: effects on amino acid pools, glucose concentration and insulin and glucagon excretion . Clin Sci Mol Med1977;52:193-204.
20.
Krzysik BA, Adibi SAComparison of the metabolism of glycine injected intravenously in free and dipeptide forms. Metabolism1979;28:1211-7.
21.
Amberger I. , Fürst P., Godel H., et al. The potential parenteral application of the peptide L-alanyl-L-glutamine as a nitrogen source in severe catabolic states. Hoppe-Seyler's Z Physiol Chem1983 ;264:1253-4.
22.
Adibi SA, Paleos GA, Morse ELInfluence of molecular structure on half life and hydrolysis of dipeptides in plasma: importance of glycine as N-terminal amino acid residue. Metabolism1986;35:830-6.
23.
Albers S., Wernerman J., Stehle P., et al. Availability of amino acids supplied intravenously in healthy humans as synthetic dipeptides: kinetic evaluation of L-alanyl-L-glutamine and glycyl-L-tyrosine. Clin Sci1988;75:463-8.
24.
Hübl W. , Druml W., Langer K., et al. Influence of molecular structure and plasma hydrolysis on the metabolism of glutamine-containing dipeptides in humans. Metabolism1989;38(suppl 5):9-62.
25.
Lochs H., Williams PE, Morse EL, et al. Metabolism of dipeptides and their constituent amino acids by liver, gut, kidney and muscle. Am J Physiol1988;254:E588-94.
26.
Abumrad NN, Morse EL, Lochs H., et al. Possible sources of glutamine for parenteral nutrition: impact on glutamine metabolism. Am J Physiol1989 ;257:E228-34.
27.
Lochs H., Roth E., Gasic S., et al. Splanchnic, renal, and muscle clearance of alanylglutamine in humans and organ fluxes of alanine and glutamine when infused in free and peptide forms. Metabolism1990;39:833-9.
28.
Lochs H., Hübl W., Gasic S., et al. Glycylglutamine: metabolism and effects on organ balances of amino acids in postabsorptive and starved subjects. Am J Physiol1992;262:E155-60.
29.
Vazquez JA, Raghunath M., Adibi SAUptake and hydrolysis of glycylglutamine at the blood brain barrier . Metabolism1992;41:121-4.
30.
Krzysik BA, Adibi SACytoplasmic dipeptidase activities of kidney, ileum, jejunum, liver, muscle and blood. Am J Physiol1977;233:E450-6.
31.
Kenney AJProteinases associated with cell membranes. In: Barrett AJ, ed. Proteinases in mammalian cells and tissues . Amsterdam: Elsevier/North Holland Biomedical Press, 1977:393-443.
32.
McDonald JK, Schwabe C.Intracellular exopeptidases. In:Barrett AJ , ed. Proteinases in mammalian cells and tissues. Amsterdam: Elsevier/ North Holland Biomedical Press, 1977:311-91.
33.
Lochs H., Morse EL, Adibi SAMechanism of hepatic assimilation of dipeptides. Transport versus hydrolysis . J Biol Chem1986;262:14976-81.
34.
Lombardo Y. , Morse EL, Adibi SASpecificity and mechanism of influence of amino acid residues on hepatic clearance of oligopeptides . J Biol Chem1988;263:12920-6.
35.
Raghunath M. , Morse EL, Adibi SAMechanism of clearance of dipeptides of perfused hindquarters: sarcolemmal hydrolysis of peptides . Am J Physiol1990;259:E463-9.
36.
Minami H., Daniel H., Morse EL, et al. Oligopeptides: mechanism of renal clearance depends on molecular structure. Am J Physiol1992;263:F109-15.
37.
Adibi SAIntestinal transport of dipeptides in humans: relative importance of hydrolysis and intact absorption. J Clin Invest1971;50:2266-75.
38.
Ganapathy V. , Leibach FH: Carrier-mediated reabsorption of small peptides in renal proximal tubule. Am J Physiol1986 ;251:F945-53.
39.
Barfuss DW, Ganapathy V., Leibach FH: Evidence for active dipeptide transport in isolated proximal straight tubules . Am J Physiol1988;255:F177-88.
40.
Daniel H., Morse EL, Adibi SAThe high and low affinity transport systems for dipeptides in kidney brush border membrane respond differently to alterations in pH gradient and membrane potential. J Biol Chem1991;266:19917-24.
41.
Daniel H., Morse EL, Adibi SADeterminants of substrate affinity for the oligopeptide/H+ symporter in the renal brush border membrane. J Biol Chem1992 ;267:9565-73.
42.
Silbernagl S., Ganapathy V., Leibach FHH+ gradient-driven dipeptide reabsorption in proximal tubule of rat kidney. Studies in vivo and in vitro . Am J Physiol1987;253:F448-57.
43.
Steinhardt HJ, Paleos GA, Brandl M., et al. Efficacy of a synthetic dipeptide mixture as the source of amino acids for total parenteral nutrition in a subhuman primate (baboon). Gastroenterology1984;86:1562-9.
44.
Vazquez JA, Paleos GA, Steinhardt HJ, et al. Protein nutrition and amino acid metabolism after 4 weeks of total parenteral nutrition with a mixture of 14 dipeptides: serendipitous observations on effects of sepsis in baboons. Am J Clin Nutr1986;44:24-32.
45.
Sax HC, Talamini MA, Fischer JFClinical use ofbranched-chain amino acids in liver disease, sepsis, trauma, and burns. Arch Surg1986;121:358-66.
46.
Vazquez JA, Paleos GA, Lochs H., et al. A concentrated mixture of amino acids and dipeptides for total parenteral nutrition. Infusion Ther1986;13:193-8.
47.
Brandl M., Sailer D., Langer K., et al. Parenteral nutrition with an amino acid solution containing a mixture of dipeptides in humans. In: Adibi SA, Fekl W, Fürst P, et al, eds. Dipeptides as new substrates in nutrition therapy. Karger: Basel, Switzerland, 1987:103-17.
48.
Albers S., Wernerman J., Stehle P., et al. Availability of amino acids supplied by constant intravenous infusion of synthetic dipeptides in healthy humans. Clin Sci1989;76:643-8.
49.
Stehle P., Mertes N., Albers S., et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet1989;1:231-3.
50.
Steininger R., Karner J., Roth E., et al. Infusion of dipeptides as nutritional substrates for glutamine, tyrosine and branched-chain amino acids in patients with acute pancreatitis. Metabolism1989;38(suppl 1):78-81.
51.
Hammarqvist F., Wernerman J., von der Decken A., et al. Alanylglutamine counteracts the depletion of free glutamine and the postoperative decline in protein synthesis in skeletal muscle. Ann Surg1990;212:637-44.
52.
Adibi SA, Krzysik BAEffect of nephrectomy and enterectomy on plasma clearance of intravenously administered dipeptides in rats. Clin Sci Mol Med1977;52:205-13.
53.
Druml W., Lochs H., Roth E., et al. Utilization of tyrosine dipeptides and acetyltyrosine in normal and uremic humans. Am J Physiol1991;260:E280-5.
54.
Rees RGP , Payne James JJ, Grimble GK, et al. Glycine nitrogen in total parenteral nutrition: two prospective clinical trials comparing the efficacy of high and low glycine containing amino acids solutions. Gut1992;33:848-54.
