C Hj



4 - Hydroxyprol ine figure B.79 L-Prolinc and 4 hydroxyprolmc

The cyclic neutral amino acid 1.-proline (2-pyrrolidinecarboxyltc acid: one-letter code P. molecular weight 115) contains 12,2% nitrogen, Hvdroxyproline is a proline metabolite with distinct properties and metabolic fate.


Hypro 4-bydroxyproline

PSC delta-l-pyrroline-5-carboxylace

PLP pyridoxal 5r-phosphate

Pro L-proline ftDA recommended dietary allowance

HIF-1 hypoxia-inducible factor 1

Nutritional summary

Function. The nonessential amino acid L-proline (Pro) is used as an energy fuel, as a precursor of L-glutamate, and for the synthesis of proteins. Its complete oxidation requires thiamin, riboflavin, niacin, vitamin B6, pantothenate. lipoate, ubiquinone, iron, and magnesium.

Food sources: Dietary proteins from different sources all contain Pro, Collagen is particularly rich in Pro. Dietary supplements containing crystalline Pro are commercially available.

Requirements: Since il can be synthesized from L-glutamate. L-glutaminc. or I -argitune. dietary intake of Pro may not be necessary as long as enough total protein is available,

Deficiency: Prolonged lack of total protein causes growth failure, loss of muscle mass anil organ damage.

Excessive intake; Very high intake of protein and mixed amino acids (more than three times the RDA or 2.4 g. kg) is thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis. Information on specific risks from high intake of Pro alone is lacking.

Endogenous sources

De novo synthesis of Pro begins with the phosphorylation of L-glutatnatc by glutamate 5-kinase ir.C2.7.2.l I}. The same bifunctiona! protein also catalyzes the next step, an NADPI l-dependent reduction (glutamate gamma-semialdehyde dehydrogenase. EC 1.2.1,41). The resulting glutamate-gamma-semialdehyde is in spontaneous equilibrium with delta l-pyrroline 5-carboxylatc which traverses the inner mitochondrial membrane by an as yet unclear mechanism. It can then be converted into Pro by NADPH-dcpendent delta l-pyrroline 5-carboxylate reductase (EC in the cytosol.

Glutamate gamma-semialdehyde is produced only in the mitochondrial matrix of the small intestine. Pro synthesis may be completed there or proceed alter transfer of the intermediate into liver cells (competing there with the synthesis of the key urea cycle metabolite L-ornithine).

4-Hydroxy proline (Hypro) arises from the post-translational modification of collagen precursor proteins by prolyl 4-hydroxylase (ECI.14.11.2. iron- and ascorbate-dependent).




COOH L-Glutamate


- > ^ - O. \ v-Glutamate "c CH_, kinase O o'

y-Glutamyl phosphate

Glutamate ^-semiaidehyde dehydrogenase h,n—ch h \

Glutamate >-semiatdehyde cooh 1




Delia 1-pyrrotine 5-carboxylate reductase

Delta 1 -pyrrol me 5-carboxytate reductase


C Ha

Delia 1-pyrroline 5-carboxylale

Figure 8 HU Endogenous synthesis of L- proline

Dietary sources

Reliable information on ihe Pro content of individual foods is very limited. There is no indication that some commonly consumed foods contain a much higher percentage of Pro than others do. Collagen in hones and connectives tissues contains about 13% llypro. About 10% of the protein in plant ceil walls consists of glycoproteins with high Hypro content.

Mow: Casein and soy protein hydrolysates in some dietary supplements contain high levels of the diketopiperazine cycto(His-Pro) which can be absorbed from the intestine (Prasad cl at., 199X). Cyclo(His-Pro), which is normally produced during the endogenous hydrolysis of thyroid-releasing hormone (TRII), affects motor functions, influences body temperature, inhibits prolactin secretion (Prasad, 19981, and might stimulate growth hormone output (Kagabu a at. 1l>98),

Digestion and absorption

Protein hydrolysis by various gastric, pancreatic, and enteral enzymes generates a mixture of free amino acids and oligopeptides. Pro-containing di- and tripeptides are efficiently taken up throughout the small intestine via the hydrogen ion peptide cotrans-porters 1 (PcpTl; SLCI5AI), and to a much lesser extent. 2 <PepT2; SLCI5A2). Free Pro and Hypro enter small intestinal cell via the sodium-dependent transporter IMINO (Urdaneta et at.. 1998); this transporter may also be chloride-dependent.

dl/tri peptides

Pro Hypro

Intestinal lumen dl/tri peptides

Pro Hypro

Intestinal lumen

Capillary lumen

Brush border membrane

Basolateral membrane

Capillary endothelium


Hypro f ao, rBAT

Capillary lumen

Brush border membrane

Basolateral membrane

Capillary endothelium

Figur* 8.81 Intestinal absorption of L-prolmt

The rBAT (SLC3AI (-anchored amino acid transporter BATI/b° ' (SLC7A9) facilitates entry by exchange with another neutral amino acid(Chairoungduaetui.. 1999); this heteroexchange can occur in either direction, depending on the prevalent concentration gradient.

Transport and cellular uptake

Blood circulation: Pro is a part of most proteins in blood and can be taken up by cells via mechanisms specific to each of them. Free Pro (about 170 jtmol/l in biood) enters tissues mainly via system L including the specifically identified heteroexchanger LATI. Typical Hypro concentrations in blood are around 10|xmol/l in people who consume meat, about half as much in vegetarians (1 lung et ul., 2002). Materno-fetal transfer Pro transfer across the microvillous membrane of the syncy-tiotrophoblast is mediated by LATI (Ritchie and Taylor. 20011, transport across the basal membrane proceeds v ia LAT2. both in exchange for other neutral amino acids (Kudo and Boyd, 2001). The driving force for LAI 1 LAI 2-mediated transport is the concentration gradient of small neutral amino acids (glycine, I -alanine, cysteine) established by the sodium-dependent transport systems A and ASC. Blood brain barrier. System I. mediates Pro transport across the neuroendolhclial cell layer. Within the brain itself the sodium chloride-dependent proline transporter (PROT) mediates uptake into neurons.


Proline: Pro breakdown in the mitochondrial matrix of muscle, liver, kidneys, and other tissues begins with its oxidation by proline dehydrogenase (proline oxidase; EC; this enzyme contains cov alently bound ADP as a functional group and uses a cytochrome c as an electron acceptor. Because some leakage of reactive oxygen species occurs, the oxidation of Pro generates free radicals (Donald et id. 2001). Sarcosin oxidase (ECI.5.3.1, contains FAD) in peroxisomes also converts Pro into delta-l-pyrrolinc-5-carboxylate (P5C). but uses oxygen and generates hydrogen peroxide (Rcuberev if/.. 1997),

1 -Pyrrolinc 5-carboxvlic acid dehydrogenase (ECU. 1,12. aldehyde dehydrogenase 4) catalyzes the second step of Pro conversion to glutamate. Alternatively, ornithine-oxo-acid aminotransferase (EC2.6.1.13, PLP-dependent) can convert the intermediate glutamate semi aldehyde into ornithine. Indeed. Pro metabolism in the small intestine is the major source of citrulline, ornithine, and arginine in the body (Wu, 1997; Dillon etui. 1999).

Hydroxyprolme The catabolism of Hypro differs from that of Pro. Hypro is derived from dietary collagen and endogenously from the turnov er of muscle, connective tissue, and bone. Most Hypro is catabolized in the epithelial cells of renal proximal tubules, smaller amounts in the liver. The amino acid reaches the mitochondria through a transloeaior that is distinct from that for Pro (Atlante et ul., 1994), The initial step is catalyzed by 4-oxoproline reductase (hydroxyproline oxidase: LCI 1.1.104) in kidney (Kim et ul..


C Hj


Sarcos me oxidase

Proline dehydrogenase (ADP)

Ox h,0, acceptor H,0

reduced acceptor COOH

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