Glycine cleavage system
| Glycine cleavage H-protein | |||||||||
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| Glycine cleavage T-protein, Aminomethyltransferase folate-binding domain | |||||||||
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| Glycine cleavage T-protein C-terminal barrel domain | |||||||||
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The glycine cleavage system (GCS) is also known as the glycine decarboxylase complex or GDC. The system is a series of enzymes that are triggered in response to high concentrations of the amino acid glycine.[1] The same set of enzymes is sometimes referred to as glycine synthase when it runs in the reverse direction to form glycine.[2] The glycine cleavage system is composed of four proteins: the T-protein, P-protein, L-protein, and H-protein. They do not form a stable complex,[3] so it is more appropriate to call it a "system" instead of a "complex". The H-protein is responsible for interacting with the three other proteins and acts as a shuttle for some of the intermediate products in glycine decarboxylation.[2] In both animals and plants, the glycine cleavage system is loosely attached to the inner membrane of the mitochondria. Mutations in this enzymatic system are linked with glycine encephalopathy.[2]
Components
| Name | EC number | Function |
|---|---|---|
| P-protein ( GLDC )
|
EC 1.4.4.2 | glycine dehydrogenase (decarboxylating) or just glycine dehydrogenase (pyridoxal phosphate) |
| T-protein (GCST or AMT) | EC 2.1.2.10 | aminomethyltransferase |
| H-protein (GCSH) | is modified with lipoic acid and interacts with all other components in a cycle of reductive methylamination (catalysed by the P-protein), methylamine transfer (catalysed by the T-protein) and electron transfer (catalysed by the L-protein).[3] | |
| L-protein (GCSL or DLD) | EC 1.8.1.4 | known by many names, but most commonly dihydrolipoyl dehydrogenase
|
Function
In plants, animals and bacteria the glycine cleavage system catalyzes the following reversible reaction:
- Glycine + H4folate + NAD+ ↔ 5,10-methylene-H4folate + CO2 + NH3 + NADH + H+
In the enzymatic reaction, H-protein activates the P-protein, which catalyzes the
When coupled to serine hydroxymethyltransferase, the glycine cleavage system overall reaction becomes:
- 2 glycine + NAD+ + H2O → serine + CO2 + NH3 + NADH + H+
In humans and most vertebrates, the glycine cleavage system is part of the most prominent glycine and serine catabolism pathway. This is due in large part to the formation
This reaction, and by extension the glycine cleavage system, is required for
In the anaerobic bacteria, Clostridium acidiurici, the glycine cleavage system runs mostly in the direction of glycine synthesis. While glycine synthesis through the cleavage system is possible due to the reversibility of the overall reaction, it is not readily seen in animals.[8][9]
Clinical significance
Glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH), is a primary disorder of the glycine cleavage system, resulting from lowered function of the glycine cleavage system causing increased levels of glycine in body fluids. The disease was first clinically linked to the glycine cleavage system in 1969.[10] Early studies showed high levels of glycine in blood, urine and cerebrospinal fluid. Initial research using carbon labeling showed decreased levels of CO2 and serine production in the liver, pointing directly to deficiencies glycine cleavage reaction.[11] Further research has shown that deletions and mutations in the 5' region of the P-protein are the major genetic causes of nonketotic hyperglycinemia. .[12] In more rare cases, a missense mutation in the genetic code of the T-protein, causing the histidine in position 42 to be mutated to arginine, was also found to result in nonketotic hypergycinemia. This specific mutation directly affected the active site of the T-protein, causing lowered efficiency of the glycine cleavage system.[13]