Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing

Abstract

Wound healing is a complex process marked by highly coordinated immune fluxes into an area of tissue injury; these are required for re-establishment of normal tissue integrity. Along with this cascade of cellular players, wound healing also requires coordinated flux through a number of biochemical pathways, leading to synthesis of collagen and recycling or removal of damaged tissues. The availability of nutrients, especially amino acids, is critical for wound healing, and enteral supplementation has been intensely studied as a potential mechanism to augment wound healing-either by increasing tensile strength, decreasing healing time, or both. From a practical standpoint, although enteral nutrient supplementation may seem like a reasonable strategy to augment healing, a number of biochemical and physiologic barriers exist that limit this strategy. In this critical review, the physiology of enteral amino acid metabolism and supplementation and challenges therein are discussed in the context of splanchnic physiology and biochemistry. Additionally, a review of studies examining various methods of amino acid supplementation and the associated effects on wound outcomes are discussed.

Keywords: amino acid supplementation; collagen metabolism; metabolism; nutrient supplementation; surgical metabolism; wound healing; wound strength.

FIGURE 1

Schematic representation of the amino acid composition of collagen. Composite from various sources; reproduced from reference with permission.

FIGURE 2

Proline and glutamate metabolism are functional links between the TCA and urea cycles. A number of enzymes and biochemical transformations link the metabolism of proline intermediates; however, many of these reactions are physically separated within the cell. Glutamine and glutamate can be interconverted by the actions of GS and GLN, respectively. The anaplerotic reaction converting glutamate to α-ketoglutarate is catalyzed by GDH and heavily favors the synthesis of α-ketoglutarate. Glutamate can alternatively be metabolized to P5C by P5CS or P5C can be metabolized to glutamate by P5CDH. P5C and GSA spontaneously interconvert with P5C and can be converted to proline via the action of P5CR, whereas the reverse reaction is catalyzed by POX that can also be referred to in some texts as PDH. Additionally, GSA can be metabolized to ornithine via OAT to replenish the urea cycle. Other urea cycle intermediates, including citrulline and arginine, can be given exogenously to produce ornithine that can be subsequently used for proline synthesis. AS, argininosuccinate; ASL, argininosuccinate lyase; CPS-I, carbamoyl phosphate synthetase I; CoA, coenzyme A; GDH, glutamate dehydrogenase; GLN, glutaminase; GS, glutamine synthase; GSA, glutamate-semialdehyde; OAA, oxaloacetic acid; OAT, ornithine aminotransferase; OTC, ornithine transcarbamylase; PDH, proline dehydrogenase; POX, proline oxidase; P5C, pyrroline-5-carboxylate; P5CDH, P5C dehydrogenase; P5CR, P5C reductase; P5CS, P5C synthase; spont., spontaneous; TCA, tricarboxylic acid.

FIGURE 3

Effect of 14-d dietary supplementation with 1% arginine (A) or ornithine (B) on wound breaking strength and wound collagen deposition in implantable dermal sponges from wild-type and iNOS KO male mice. *,**Significant differences from control, P < 0.05 and P < 0.01, respectively (Student’s t test). Values are means ± SEs; n = 10–12/group. iNOS, inducible NO synthase; KO, knockout. Composite adapted from references and with permission.