The glycine deportation system and its pharmacological consequences.

Abstract

The glycine deportation system is an essential component of glycine catabolism in man whereby 400 to 800mg glycine per day are deported into urine as hippuric acid. The molecular escort for this deportation is benzoic acid, which derives from the diet and from gut microbiota metabolism of dietary precursors. Three components of this system, involving hepatic and renal metabolism, and renal active tubular secretion help regulate systemic and central nervous system levels of glycine. When glycine levels are pathologically high, as in congenital nonketotic hyperglycinemia, the glycine deportation system can be upregulated with pharmacological doses of benzoic acid to assist in normalization of glycine homeostasis. In congenital urea cycle enzymopathies, similar activation of the glycine deportation system with benzoic acid is useful for the excretion of excess nitrogen in the form of glycine. Drugs which can substitute for benzoic acid as substrates for the glycine deportation system have adverse reactions that may involve perturbations of glycine homeostasis. The cancer chemotherapeutic agent ifosfamide has an unacceptably high incidence of encephalopathy. This would appear to arise as a result of the production of toxic aldehyde metabolites which deplete ATP production and sequester NADH in the mitochondrial matrix, thereby inhibiting the glycine deportation system and causing de novo glycine synthesis by the glycine cleavage system. We hypothesize that this would result in hyperglycinemia and encephalopathy. This understanding may lead to novel prophylactic strategies for ifosfamide encephalopathy. Thus, the glycine deportation system plays multiple key roles in physiological and neurotoxicological processes involving glycine.

• Authors: Diren Beyoğlu, Jeffrey R Idle
• Journal: Pharmacology & therapeutics (Pharmacol Ther) Vol. 135 Issue 2 Pg. 151-67 (Aug 2012) ISSN: 1879-016X [Electronic] England
• PMID: 22584143 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Multienzyme Complexes
• glycine cleavage system
• Benzoic Acid
• Amino Acid Oxidoreductases
• Transferases
• Glycine

Topics

• Amino Acid Oxidoreductases (metabolism)
• Animals
• Benzoic Acid (metabolism)
• Carrier Proteins (metabolism)
• Glycine (metabolism)
• Homeostasis
• Humans
• Multienzyme Complexes (metabolism)
• Transferases (metabolism)