[ Vol. 1 No. 3 ] (September - December 2000 )
Synthetic Dipeptides - A New Dimension in Clinical Nutrition

Prof.Peter Furst, MD, PhD.
Institute of Biological Chemistry and Nutrition, University of Hohenheim, Stuttgart/Germany.

Recent investigations clearly indicate that certain amino acids previously considered as non-essential are conditionally indispensable substrates in various diseased states: Hypermetabolic and hypercatabolic situations are accompanied by a marked depression of the intracellularglutaminepool. This depletion of glutamine stores leads to severe complications, such as infection, poor wound healing, impaired immunity, increased intestinal permeability, and finally multiple organ failure. In the liver tissue of fetuses and preterm and term infants the endogenous synthesis of the sulfur containing amino acidcysteineis impaired due to low or undetectable activity of the key enzyme cystathionase. Low intracellular concentrations oftaurineare a typical feature in chronic renal failure and presumably associated with muscle fatigue. Under certain pathological conditions like phenylketonuria, liver and kidney diseases, and in premature infants the aromatic amino acidtyrosineis considered conditionally indispensable due to impaired synthesis from phenylalanine. These data strongly support the notion that glutamine, cysteine/cystine, taurie, and tyrosine should be essential parts of artificial nutrition in various diseased states. However, unfavourable physical/chemical properties as well as metabolic limitation hamper their use as parenteral substrates in routine clinical setting. Glutamine quantitatively decomposes in aqueous solutions during heat sterilization and long-term storage to yield pyroglutamic acid and ammonia. In addition, provision of free glutamine in adeqate amounts to patients is always associated with a high water load due to its limited solubility. Tyrosine and cystine are poorly soluble (only 0.4 and 0.1 g/L H2O, respectively); cysteine rapidly oxidizes to yield cystine. Parenteral free taurine minght not be available for the depleted intracellular compartment because of a low transport rate due o the very high intracellular/extracllular transmembrane gradient.

Synthesis and characerization of synthetic dipeptides
These obvious drawbacks have initiated an intensive research for alternative substrates which can be used as amino acid sources in parenteral and enteral nutrition. In cooperation with our industry partners (Degussa AG, Fresenius Kabi) we successfully developed in our working group chemical/biotechnological methods for the synthesis of glutamine-, cystine-, tyrosine- and taurine-containing dipeptides/conjugates. All synthetic peptides were highly soluble and showed purity degrees better than 99%. Carefully controlled studies confirmed the stability of the peptides during sterilization and storage. In the meantime, the synthetic process has been scaled up for selected peptides (glutamine and tyrosine dipeptides) to yield industrial quantities.

Dipeptide utilization - experimental studies
Basic studies with various synthetic glutamine-, tyrosine- and cystine-containing dipeptides provide convincing evidence that these substrates are rapidly cleared from plasma after parenteral administration without accumulating in tissues and with minimal losses in urine. The presence of membrane-bound as well as tissue free extracellular hydrolase activity facilitates a prompt and quantitative peptide hydrolysis, the liberated amino acids being available for protein synthesis and/or generation of energy.

Dipeptide utilization - human studies
Human studies in healthy volunteers demonstrated that the synthetic glutamine dipeptides L-glutamine (Ala-Gln, present in Dipeptiven®) and glycyl-L-glutamine (Gly-Gin, Present in Glamin®) as well as the synthetic tyrosine dipeptide glycyl-L-tyrosine (Gly-Tyr, present in Glamin®) are rapidly hydrolyzed after bolus injection (elimination half lives 3., 7.8, and 3.8 min, respectively). Continuous infusion of a  commercial amino acid solution supplemented with Ala-Gln or Gly-Gln was not accompanied by any side effects, and no complaints were reported. Infusion of peptide-supplemented solutions resulted in a prompt increase in alanine, glutamine, tyrosine and glycine concentrations. During the entire infusion period, only trace amounts of the dipeptides of the dipeptides could be measured in plasma. Urinary losses of dipeptids were only approximately 1% of the given dose. These results indicate a near-quantitative hydrolysis of the infused peptide, with subsequent utilization of the constituent free amino acids.

The dipeptide concept - a milestone in patient care
The provision of conditionally indispensable amino acids like glutamine and others must be considered as a necessary replacement of a deficiency rather than a supplementation. The beneficial effects observed with dipeptide nutrition should be seen simply as a correction of disadvantages produced by the inadequacy of conventional clinical nutrition. The availability of stable dipeptide preparations certainly facilitate for the first time an adequate amino acid nutrition of critically ill, malnourished or stressed patients in the routine clinical setting and, thus, represents a new dimension in artificial nutrition.