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38  structures 7109  species 0  interactions 10043  sequences 60  architectures

Family: GCV_H (PF01597)

Summary: Glycine cleavage H-protein

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This is the Wikipedia entry entitled "Glycine cleavage system". More...

Glycine cleavage system Edit Wikipedia article

Glycine cleavage H-protein
PDB 1hpc EBI.jpg
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
Symbol GCV_H
Pfam PF01597
Pfam clan CL0105
InterPro IPR002930
SCOP 1htp
Glycine cleavage T-protein, Aminomethyltransferase folate-binding domain
PDB 1v5v EBI.jpg
crystal structure of a component of glycine cleavage system: t-protein from pyrococcus horikoshii ot3 at 1.5 a resolution
Symbol GCV_T
Pfam PF01571
Pfam clan CL0289
InterPro IPR006222
SCOP 1pj5
Glycine cleavage T-protein C-terminal barrel domain
PDB 1wor EBI.jpg
crystal structure of t-protein of the glycine cleavage system
Symbol GCV_T_C
Pfam PF08669
InterPro IPR013977
SCOP 1pj5

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]


Name EC number Function
T-protein (GCST or AMT) EC aminomethyltransferase
P-protein (GLDC) EC glycine dehydrogenase (decarboxylating) or just glycine dehydrogenase.
L-protein (GCSL or DLD) EC known by many names, but most commonly dihydrolipoyl dehydrogenase
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]


Glycine cleavage

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 decarboxylation 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 uses tetrahydrofolate and yields ammonia and 5,10-methylenetetrahydrofolate. After interaction with the T-protein, the H-protein is left with two fully reduced thiol groups in the lipoate 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 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 5,10-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 as purines and methionine.

Glycine and serine catabolism in and out of the mitochondria. Inside the mitochondria, the glycine cleavage systems links to the serine hydroxymethyltransferase in a reversible process allowing for flux control in the cell.

This reaction, and by extension the glycine cleavage system, is required for photorespiration in C3 plants. The glycine cleavage system takes glycine, which is created from an unwanted byproduct of the Calvin cycle, and converts it to serine which can reenter the cycle. The ammonia generated by the glycine cleavage system, is assimilated by the Glutamine synthetase-Glutamine oxoglutarate aminotransferase cycle but costs the cell one ATP and one NADPH. 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 in mitochondria from spinach and pea leaves.[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]

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]

See also


  1. ^ Kikuchi G (June 1973). "The glycine cleavage system: composition, reaction mechanism, and physiological significance". Mol. Cell. Biochem. 1 (2): 169–87. doi:10.1007/BF01659328. PMID 4585091. 
  2. ^ a b c d Kikuchi G (2008). "The glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia". Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 84 (7): 246–63. doi:10.2183/pjab.84.246. PMC 3666648Freely accessible. PMID 18941301. 
  3. ^ a b c Douce R, Bourguignon J, Neuburger M, Rébeillé F (April 2001). "The glycine decarboxylase system: a fascinating complex". Trends Plant Sci. 6 (4): 167–76. doi:10.1016/S1360-1385(01)01892-1. PMID 11286922. 
  4. ^ Fujiwara K, Okamura K, Motokawa Y (Oct 1979). "Hydrogen carrier protein from chicken liver. Purification, characterization, and role of its prosthetic group, lipoic acid, in the glycine cleavage reaction". Arch. Biochem. Biophys. 197 (2): 454–462. doi:10.1016/0003-9861(79)90267-4. PMID 389161. 
  5. ^ Pares S, Cohen-Addad C, Sicker L, Neuburger M, Douce R (May 1994). "X-ray structure determination at 2.6A˚ resolution of a lipoate-containing protein. The H-protein of the glycine decraboxylase complex from pea leaves". Proc. Natl. Acad. Sci. U.S.A. 91 (11): 4850–3. doi:10.1073/pnas.91.11.4850. PMC 43886Freely accessible. PMID 8197146. 
  6. ^ Fujiwara K, Okamura-Ikeda K, Motokawa Y (Sep 1984). "Mechanism of the glycine cleavage reaction. Further characterization of the intermediate attached to H-protein and of the reaction catalyzed by T-protein". J. Biol. Chem. 259 (17): 10664–8. PMID 6469978. 
  7. ^ Oliver DJ, Neuburger M, Bourguignon J, Douce R (Oct 1990). "Interaction between the component enzymes of the glycine decarboxylase mutienzyme complex". Plant Physiology. 94 (4): 833–839. doi:10.1104/pp.94.2.833. PMC 1077305Freely accessible. PMID 16667785. 
  8. ^ Gariboldi RT, Drake HL (May 1984). "Glycine synthase of the purinolytic bacterium Clostridium acidiurici. Purification of the glycine-CO2 exchange system". J. Biol. Chem. 259 (10): 6085–6089. PMID 6427207. 
  9. ^ Kikuchi G, Hiraga K (June 1982). "The mitochondrial glycine cleavage system. Unique features of the glycine decarboxylation". Mol. Cell. Biochem. 45 (3): 137–49. doi:10.1007/bf00230082. PMID 6750353. 
  10. ^ Yoshida T, Kikuchi G, Tada K, Narisawa K, Arakawa T (May 1969). "Physiological significance of glycine cleavage system in human liver as revealed by the study of hyperglycinemia". Biochem. Biophys. Res. Commun. 35 (4): 577–83. doi:10.1016/0006-291x(69)90387-8. PMID 5788511. 
  11. ^ Hayasaka K, Tada K, Fueki N, Nakamura Y (June 1987). "Nonketotic hyperglycinemia: analyses of glycine cleavage system in typical and atypical cases". J. Pediatr. 110 (6): 873–7. doi:10.1016/S0022-3476(87)80399-2. PMID 3585602. 
  12. ^ Kanno J, Hutchin T, Kamada F, Narisawa A, Aoki Y, Matsubara Y, Kure S (Mar 2007). "Genomic deletion within GLDC is a major cause of non-ketotic hyperglycinaemia". Journal of Medical Genetics. 44 (3): e69. doi:10.1136/jmg.2006.043448. PMC 2598024Freely accessible. PMID 17361008. 
  13. ^ Kure S, Mandel H, Rolland MO, Sakata Y (April 1998). "A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia". Hum. Genet. 102 (4): 430–4. doi:10.1007/s004390050716. PMID 9600239. 

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Glycine cleavage H-protein Provide feedback

This is a family of glycine cleavage H-proteins, part of the glycine cleavage multienzyme complex (GCV) found in bacteria and the mitochondria of eukaryotes. GCV catalyses the catabolism of glycine in eukaryotes. A lipoyl group is attached to a completely conserved lysine residue. The H protein shuttles the methylamine group of glycine from the P protein to the T protein.

Literature references

  1. Pares S, Cohen-Addad C, Sieker L, Neuburger M, Douce R; , Proc Natl Acad Sci U S A 1994;91:4850-4853.: X-ray structure determination at 2.6-A resolution of a lipoate- containing protein: the H-protein of the glycine decarboxylase complex from pea leaves. PUBMED:8197146 EPMC:8197146

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR033753

This is a family of glycine cleavage H-proteins, part of the glycine cleavage system (GCS) found in bacteria, archaea, and the mitochondria of eukaryotes. GCS is a multienzyme complex consisting of 4 different components (P-, H-, T- and L-proteins) which catalyzes the oxidative cleavage of glycine [ PUBMED:11286922 ]. The H-protein shuttles the methylamine group of glycine from the P-protein (glycine dehydrogenase) to the T-protein (aminomethyltransferase) via a lipoyl group, attached to a completely conserved lysine residue [ PUBMED:8197146 ].

This enty includes Abitram proteins. Abitram (also known as Simiate) functions in transcription regulation [ PUBMED:24349419 ]. Furthermore, it associates with both G- and F-Actin and affects actin polymerization and actin turnover, influencing filopodia dynamics and arborization of neurons [ PUBMED:24782708 ].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Hybrid (CL0105), which has the following description:

This superfamily contains proteins with a hybrid motif [1]. This motif is embedded in structurally diverse proteins.

The clan contains the following 25 members:

Apocytochr_F_C Biotin_carb_C Biotin_lipoyl Biotin_lipoyl_2 Complex1_51K CusB_dom_1 DUF2118 DUF2254 GARS_C GCV_H HlyD_2 HlyD_3 HlyD_D23 HlyD_D4 HMBD LAL_C2 NAPRTase_N NQRA OEP Peptidase_M23 PTS_EIIA_1 PurK_C PYNP_C QRPTase_N RnfC_N


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_988 (release 4.1)
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 13
Number in full: 10043
Average length of the domain: 117.90 aa
Average identity of full alignment: 40 %
Average coverage of the sequence by the domain: 80.84 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.2 22.2
Trusted cut-off 22.2 22.2
Noise cut-off 22.1 22.1
Model length: 122
Family (HMM) version: 21
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Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GCV_H domain has been found. There are 38 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2JYW6 View 3D Structure Click here
A0A0G2JZ02 View 3D Structure Click here
A0A0R0E5J0 View 3D Structure Click here
A0A0R0J5R5 View 3D Structure Click here
A0A0R0JD84 View 3D Structure Click here
A0A0R4J4A7 View 3D Structure Click here
A0A1D6HUY3 View 3D Structure Click here
A0A1D6IUW7 View 3D Structure Click here
A0A1D6P6W3 View 3D Structure Click here
A0A1D6QSC9 View 3D Structure Click here
A0A1X7YEC2 View 3D Structure Click here
A0JQ11 View 3D Structure Click here
A3C6G9 View 3D Structure Click here
A4IC11 View 3D Structure Click here
B4FUR6 View 3D Structure Click here
C6T0B7 View 3D Structure Click here
C7IY93 View 3D Structure Click here
D4AE08 View 3D Structure Click here
F1QRR5 View 3D Structure Click here
I1JT02 View 3D Structure Click here
I1K7H5 View 3D Structure Click here
I1NDC6 View 3D Structure Click here
K7TZ76 View 3D Structure Click here
O62122 View 3D Structure Click here
O82179 View 3D Structure Click here
P0A6T9 View 3D Structure Click here
P23434 View 3D Structure Click here
P25855 View 3D Structure Click here
P39726 View 3D Structure Click here
P9WN55 View 3D Structure Click here
Q1LU93 View 3D Structure Click here
Q20634 View 3D Structure Click here
Q2FZZ8 View 3D Structure Click here
Q2G150 View 3D Structure Click here
Q4CS26 View 3D Structure Click here
Q4E4F5 View 3D Structure Click here
Q54FI0 View 3D Structure Click here
Q54JU0 View 3D Structure Click here
Q54JU1 View 3D Structure Click here
Q54JU3 View 3D Structure Click here
Q54JV8 View 3D Structure Click here
Q5AKX1 View 3D Structure Click here
Q5I0P2 View 3D Structure Click here
Q655T6 View 3D Structure Click here
Q6DGX4 View 3D Structure Click here
Q6H713 View 3D Structure Click here
Q80ZQ9 View 3D Structure Click here
Q8II35 View 3D Structure Click here
Q91WK5 View 3D Structure Click here
Q9HDV9 View 3D Structure Click here
Q9LQL0 View 3D Structure Click here
Q9NX38 View 3D Structure Click here
Q9U616 View 3D Structure Click here
Q9VFR1 View 3D Structure Click here