Glycine cleavage H-protein
refined structures at 2 angstroms and 2.2 angstroms of the two forms of the h-protein, a lipoamide-containing protein of the glycine decarboxylase
Identifiers
Symbol	GCV_H
Pfam	PF01597
Pfam clan	CL0105
InterPro	IPR002930
SCOP2	1htp /SCOPe /SUPFAM
Available protein structures: PDB   IPR002930PF01597 (ECOD;PDBsum)   AlphaFold IPR002930 PF01597

Glycine cleavage T-protein, Aminomethyltransferase folate-binding domain
crystal structure of a component of glycine cleavage system: t-protein from pyrococcus horikoshii ot3 at 1.5 a resolution
Identifiers
Symbol	GCV_T
Pfam	PF01571
Pfam clan	CL0289
InterPro	IPR006222
SCOP2	1pj5 /SCOPe /SUPFAM
Available protein structures: PDB   IPR006222PF01571 (ECOD;PDBsum)   AlphaFold IPR006222 PF01571

Glycine cleavage T-protein C-terminal barrel domain
crystal structure of t-protein of the glycine cleavage system
Identifiers
Symbol	GCV_T_C
Pfam	PF08669
InterPro	IPR013977
SCOP2	1pj5 /SCOPe /SUPFAM
Available protein structures: PDB   IPR013977PF08669 (ECOD;PDBsum)   AlphaFold IPR013977 PF08669

Theglycine cleavage system (GCS) is also known as theglycine decarboxylase complex orGDC. The system is a series of enzymes that are triggered in response to high concentrations of the amino acidglycine.^[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 withglycine encephalopathy.^[2]

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 thedecarboxylation of glycine and attaches the intermediate molecule to the H-protein to be shuttled to the T-protein.^[4][5] The H-protein forms a complex with the T-protein that usestetrahydrofolate and yieldsammonia and5,10-methylenetetrahydrofolate. After interaction with the T-protein, the H-protein is left with two fully reducedthiol groups in thelipoate group.^[6] The glycine protein system is regenerated when the H-protein is oxidized to regenerate the disulfide bond in the active site by interaction with the L-protein, which reduces NAD⁺ to NADH and H⁺.

When coupled toserine 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 formation5,10-methylenetetrahydrofolate, which is one of the few C₁ donors in biosynthesis.^[2] In this case the methyl group derived from the catabolism of glycine can be transferred to other key molecules such aspurines andmethionine.

This reaction, and by extension the glycine cleavage system, is required forphotorespiration in C₃ plants. The glycine cleavage system takes glycine, which is created from an unwanted byproduct of theCalvin cycle, and converts it toserine which can reenter the cycle. The ammonia generated by the glycine cleavage system, is assimilated by theGlutamine synthetase-Glutamine oxoglutarate aminotransferase cycle but costs the cell oneATP and oneNADPH. The upside is that one CO₂ is produced for every two O₂ that are mistakenly taken up by the cell, generating some value in an otherwise energy depleting cycle. Together the proteins involved in these reactions comprise about half the proteins inmitochondria fromspinach andpealeaves.^[3] The glycine cleavage system is constantly present in the leaves of plants, but in small amounts until they are exposed to light. During peak photosynthesis, the concentration of the glycine cleavage system increases ten-fold.^[7]

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]

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 usingcarbon 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 thehistidine in position 42 to be mutated toarginine, 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]

• dihydrolipoamide dehydrogenase
• lipoic acid
• glycine encephalopathy

• Cellular respiration
• NADH-dependent enzymes
• Enzymes of unknown structure

• Articles with short description
• Short description is different from Wikidata