DihydrolipoamideN dehydrogenase (FAD)




DihydrolipoamideN dehydrogenase (FAD)


Glycine dehydrogenase, decartooxyiatin (TPP)

Glycine dehydrogenase, decartooxyiatin (TPP)

5,10 methylene THF THF



Serine hydroxy-methy I trans (erase



Cysteine Phospholipids

Figure 8.18 Glycine metabolism


Purines Porphyhns Sarcos i ne







Kynureriine |Trp)


Glyoxylate reabsorption the ioss of Gly into urine is minimal in healthy people. Losses into feces are negligible while gastrointestinal function is normal.

Nitrogen from metabolized Gly is excreted into urine as urea or as uric acid. Nearly a quarter of the nitrogen in uric acid comes from Gly.


Gly homeostasis is maintained through modulation of overall protein synthesis and breakdown. and through changes in the activities of the giy cine-cleavage system (EC2.I.2.I I




1 Adenosine nucleotides

Figure 8.19 Glycine it a precursor of purine nucleotides and glycine hydroxymethyltransferasc (I-C2.1.2.1>, Glucagon promotes Gly catabolism in the liver by stimulating the glycine-cleavage system (Jois et ai. 1989).


Energy fuel. Daily Gly oxidation is about cM)mg'kg body weight (Gibson el al.. 2t>02 f. The glycine-cleavage system (glycine dehydrogenase; EC generates one NADU and one 5.10-metbylene-THF per metabolized Gly molecule. Transfer of the one-carbon unit from 5.10-methylene-THFto another Gly molecule generates serine, which can then be utilized \ ia pyruvate. The energy yield from complete oxidation is 2.011 kcal g (May and Dili. I990i, requiring adequate supplies of thiamin, riboflavin, niacin, vitamin 130. folate. \ itamin HI2. pantothenate, lipoatc, ubiquinone, iron, and magnesium. Protein synthesis: Glyeine-tRNA ligasc (E( '6,1,1.14) loads t ily to its specific tRNA for protein synthesis.

Methionine metabolism: One-carbon transfer from S-adenosyl methionine (SAM) to glycine by glycine N-methy I transferase (EC2.1.1.20) plays a crucial role in methionine metabolism that tsnoi completely understood, yet. l.aek of enzyme causes hyper-methiomnemia and mild liver enlargement.

Glutathione synthesis: Gly is one of the three amino acids that make up the vital antioxidant peptide glutathione (GSH), The second step of GSM synthesis, catalyzed by glutathione synthase (EC6.3.2.3), links Gly to gamma-1 -glutamyl-! -cysteine Porphyrme synthesis: Condensation of succinyl-CoA and Gly by 5-ammolevulimc acid synthase (EC2.3.1.37) prov ides the initial precursor for porphyrins. Purine synthesis: fwo of the four carbons and one of the nitrogen atoms in purines come from Gly. The second step of tie now purine synthesis links Gly to phosphori-bosylamine in an ATP-dependent reaction catalyzed by phosphoribosylamine-glycine ligase (GAR synthetase: EC6.3.4.13).

Creatine synthesis: About 5 mg Gly kg body weight is used for daily creatine synthesis. Glycine amidinotransferase (EC2.I.4.I) in the kidneys condenses Glv and argi-nine (Wyss and Kaddurah-Daouk. 2000). The resulting guanidinoacetic acid is then methylated in an S-adenosvlmethionine-dependent reaction by guanidinoacetate N-niethy I transferase (EC2.1.I.2) in the liver.

Bile acid conjugation: Prior to secretion into the bile duct a large proportion of the bile acids is conjugated by glycine N-cho!oy I transferase (bile acid-CoAaniino acid

N-acy lirans I erase. BAT; I ( in liver microsomes. While most of the bile acids are recovered from the ileum as free acids, the extent of Gly recovery is not clear. Detoxification: Many nutrient metabolites and xenobiotics (e.g.. salicylates) arc conjugated to Gly. For example, conjugation of Gly to benzoyl-CoA by glycine N-acyltransferase (EC2.3.l.l3)and hv glycine N-benzoy I transferase (EC2.3.1.71) generates hippurate. Patients with genetic urea cycle disorders sometimes respond well to benzoate intakes, which can enhance nitrogen elimination as hippurate. Brain function: Gly is a major inhibitory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA) receptor in brain activates its ion channel when both Gly and glutamate bind to it.

Biomarker of dietary availability

Urinary 5-hydroxyproline excretion is related to Gly availability; this measure is also influenced by sulfur amino acid availability (Metges el al., 2000).


Anand RJ, Kan war U. Sanyal SN, Transport of glycine in the brush border and basal eel) membrane vesicles of the human term placenta. Biochem Mot BinI Int 199ft; 38:21-30

Avissar NE, Ryan CK, Ganapathy V. Sax HC. Na' -dependent neutral amino acid transporter AT Bo is a rabbit epithelial cell brush border protein. Am J Physiol Cell Physiol 200| ;281 :C963 71

Barker GA. Wilkins RJ, Ciolding S. 1-1 lory JC. Neutral amino acid transport in bovine articular chondrocytes../ Physiol 1999:514:795-808 Cetin I. Amino acid intercom ersions in the fetal-placenta I unit: the animal model and human studies in vivo. Ped Res 2001 ;49:148 -53 Christie GR. Ford l>. Howard A, Clark MA. Hirst BH. Glycine supply to human entero-cytes mediated by high-affinity basolateral GLYT1. Gastroenterol 2(K)I;120:439 4X Gibson NR. Jalioor F. Ware L, Jackson AA. Endogenous glycine and tyrosine production is maintained in adults consuming a marginal-protein diet hn J Clin Nutr 2002; 75:511-18

Jansson T. Annuo acid transporters in the human placenta. Pediatr Res 200l;49:14l 7 Jois M. Hall B. Fewer K, Brosnan JT. Regulation of hepatic glycine catabolism by glucagon. J BioI Client 1989;264:3347-51 May Ml:. Hill JO Energy content of diets of variable amino acid composition. 4m J Clin Nutr 1990;52:770-6

MetgesCC. Yu YM. Cai W. Lu XM. WongS. Regan MM. Ajarni A. Young VR. Oxoproline kinetics and oxoproline urinary excretion during glycine- or sulfur amino acid-free diets in humans. Am J Pliysiot Endocrinol Metah 2000;278:E868-E876 Rchan G, Kansal VK, Sharma li. Mechanism of glycine transport in mouse mammary tissue. J Dairy Res 2000;67:475- 83 Wyss M. Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000:80: 1107 2)3


The neutral essential amino acid alcohol [..-threonine (2-a mino-3-hydroxybutyric acid, a I pha-amino-beta-hydroxy butyric ac i d,2-amino-3-hy droxybul ano ic acid, one-letter code T: molecular weight 119) contains 11.8% nitrogen.


CoA coenzyme A

PepTI hydrogen lon/peptide cotrans porter 1 (SL.C15A1) RDA recommended dietary allowance Thr L-tlireonine

Nutritional summary

Function: The essential amino acid (.-threonine (Thr) is needed for the synthesis of proteins, is a precursor of glycine, and serves as an energy fuel depending on adequate supplies of thiamin, riboflavin, niacin, \iiamin U6. vitamin li 12. biotin. pantothenate, lipoate, ubiquinone, iron, and magnesium.

Food sources: Adequate amounts are consumed when total protein intakes meet recommendations. Dietary proteins from different sources all contain Thr, but animal and bean proteins have a slightly higher content (4-5% of total protein) than grain proteins (3-4% of total protein).

Requirements: The Thr requirement of adults is thought to be over 500 mg/day. Deficiency: Prolonged lack of Thr as of all essentia) amino acids or a lack of protein causes growth failure, loss of muscle mass and organ damage. Excessive intake: Very high intake of protein and mixed amino acids (more than three times the RDA or 2.4 gkg) is thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis.

Endogenous sources

Thr is an essential nutrient in humans since no metabolic pathways allowing net Thr synthesis have been detected.

Dietary sources

The Thr content of most food proteins is about 41-45 mg/g, slightly more in eggs (4,Smg g). Wheat (30 mg/g). oats (34mg/g). rice (36mg/g), com (38mg g) and other grains have a slightly lower content. At adequate dally protein intakes (0,8 g kg body weight), Thr requirements (above 500mg.d) arc certain to be exceeded several-fold. Heating foods to high temperatures causes slight losses of Thr (Pworschak. 1980), cooh !

Figure 11.20


Digestion and absorption

As food passes through the digestive tract, gastric and pancreatic enzymes continue protein breakdown, many of them cleaving peptide bonds between specific amino acids and Thr.

Thr is taken up from the small intestinal lumen by the sodium amino acid cotransport systems B" and ASC (Munck and Munck, 1999; Avissar el al.. 2001). Thr as a component of di- or tripeptides can also Ik- taken up via hydrogen ion peptide cotransportcr 1 (SLC15A1. Pep ! 1) and, to a lesser extent, 2 (SLC15A2, Pep 12),

Export across the basolateral membrane uses the sodium-ammo acid cotransport systems A (ATA2 land ASC (ASC'T I). and possibly the incompletely characterized sodium-independent system asc. As long as the amino acid concentration inside the cell i- higher than in the basolateral space, transport can occur against the considerable sodium gradient, When the intracellular amino acid concentration falls below blood levels during fasting. transport turns towards the enterocyte and supplies needed amino acids.

Both the brush border membrane and the basolateral membrane contain transporters that exchange amino acids. Neutral amino acids that are enriched in the cell by sodium cotransporters are exchanged for a wide spectrum of other amino acids. This means that net Thr transport via the heteroexchangers is in the direction of intestinal lumen. The heieroexehanger in the brush border membrane is the rBAT (SLC3A1) glycoprotein-anchored transporter BAT I b" (SLC7A9), On the basolateral side are the transporters LAT2. y1 LATI. and y LAT2, all of them anchored to the membrane by glycoprotein 4F2 (SLC3A2).

Intestinal lumen di/ui peptides neutral ammo i

Intestinal lumen neutral ammo i

Capillary lumen

Brush border membrane

Basolateral membrane

Capillary endothelium

Figure 8.21 Intestinal absorption of L-ttireonme

Capillary lumen

Brush border membrane

Basolateral membrane

Capillary endothelium

Figure 8.21 Intestinal absorption of L-ttireonme

Transport and cellular uptake

Blood circulation: Plasma concentration ofThr (typically around 128 pmol I) increases significantly after meals and is lowest during the early morning hours < isai and Huang. 1999). Uptake from blood into tissues occurs via an array of transporters, many of them identical or similar to those described for intestinal absorption. Expression patterns vary greatly between different cell types.

Materno-fetal transfer: Uptake ofThr from maternal blood across the brush border membrane of the syncytiotrophoblast is mediated by the sodium amino acid cotransporl system A (possibly also ASC and N). and the sodium-independent system L. Transfer across the basolateral membrane proceeds via the sodium amino acid cotransporl system A, and the sodium-independent transporters I.ATI and LAT2. Blood brain barrier: LAT1 is expressed in brain capillary endothelial cells and certain to contribute to Ala transport, but its relative importance and the role of other transporters are not completely understood.


Cytosol: The main flux ofThr catabolism occurs in cytosol with generation of CO; and propionyl-CoA (Darling el al., 1997). This pathway starts with the pyridoxal-phosphate-dependent deamination ofThr by threonine dehydratase (EC4.2.1.I6) followed by decarboxylation of alpha-ketobutyrate to proptonyl CoA; both pyruvate dehydrogenase (EC3.1.3.43) and branched-chain alpha-ketoaeid dehydrogenase (EC can catalyze the second reaction, both enzymes require thiamin pyrophosphate, lipoic acid, and coenzyme A. Cleavage into glycine and acclaldehyde by the two PLP-containing eytosolic enzymes threonine aldolase (EC4.I.2.5) and glycine hydroxymethy I transferase (EC2.1.2.1) appears to contribute only minimally to threonine breakdown (Ogawa et al.. 2000).

Mitochondria: The threonine cleavage complex generates acetyl-C'oA and glycine in a two-step sequence. L.-threonine dehydrogenase (EC 1.1,103) oxidizes Thr to 2-amino 3-ketobutyratc. The PLP-depcndent 2-amino-3-ketobutyrate coenzyme A ligasc (FX links the acetyl moiety to CoA and cleaves oft glycine. Both acetyl-CoA and glycine then can be utilized via their respective usual pathways.

2-Amino-3-ketobutyrate also can spontaneously decarboxyiate to aminoacetone which is deaminated by FAD-dependent semicarbazide-sensitive amine oxidase (EC With increasing availability ofThr or with low availability of free CoA a greater proportion enters this alternative pathway. The cytotoxic metabolite methyl-glvoxal can be converted to either acetol or lactaldehyde by aldehyde reductase (EC, the relative proportions depending on reduced glutathione concentration (Vander Jagt et ai. 2001). Alternatively, methylglyoxal can spontaneously form a hemithioacetal complex with glutathione which is a preferred substrate for lactoyl-glutathionc lyase [glyoxalase I; EC'4.4.1,5). This zinc enzyme generates lactoy[glutathione which, in turn, is converted by another zinc enzyme, hydroxyacylglutathione hydrolase (glyoxalase II; EC3,1.2.6) to the dead-end metabolite D-lactatc, Preference


CH, L-Threonine



Pyruvate OH or branch«! 1 CH, cKiir ,,-koro acid OH CH, u-Kelobutyrate itPPiüpooiel PropuonytCoA

Tfirayune dehydro-gansja

CH, 2-Amino 3'kelobutyralo nan- I

enzymatic CO )

CH, Aminoacerono

Amine aildBse L (FAD)

CH, Meiliyiglyoxal

2-Amino-3-iwiKi' butyraie lyase (PLPj



CM, Glycine

J [ttiOtin]


COOH Suconyl-CoA


CH S-glutattwx»

CK, Methylglyoxal-glutalhiono

Giyoiaiase I


Aldose Y NADPH reductase 2 [


Glyona V g^UMd 1 ■ gknamnrtd


CH-OH CH, □-lactate figure 8,12 Metabolism of L-threonine for this glyoxaiase pathway increases with higher glutathione concentrations (Vander Jagt ei a!., 2001).


Assuming an average Thr content of human proteins of 48 mg g (Smith. 1^8(1). a 70 kg man may have a mobilizablc reserve of about 288 g. The Thr content of hemoglobin is 59 mg/g, At a hypothetical breakdown rate of 20 ml red blood cells or 6g hemoglobin per day this would correspond to a daily release of 354 mg Thr


Filtered free Thr i> taken up into proximal renal tubules by sodium-ami no acid cotrans-port systems B"and ASC (Avjssareral., 20(H). di-and tnpeptides via PepTI and PepT2.

As in the small intestine, the various hetcrocxchangers tend to use Thr as a counter-molecule tor the transport of other amino acids. Nonetheless, recovery ofThr tends to nearly complete in healthy people Losses into feces also are negligible w hen gastrointestinal function is normal.

Most nitrogen from metabolized Thr is excreted into tirine as urea. Aminoacetone and D-lactate are minor metabolic products whose urinary excretion increases disproportionately with high Thr intakes and when availability of free CoA is limited.



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