Glycine cleavage system

Last updated
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
Identifiers
SymbolGCV_H
Pfam PF01597
Pfam clan CL0105
InterPro IPR002930
SCOP2 1htp / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
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
Identifiers
SymbolGCV_T
Pfam PF01571
Pfam clan CL0289
InterPro IPR006222
SCOP2 1pj5 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Glycine cleavage T-protein C-terminal barrel domain
PDB 1wor EBI.jpg
crystal structure of t-protein of the glycine cleavage system
Identifiers
SymbolGCV_T_C
Pfam PF08669
InterPro IPR013977
SCOP2 1pj5 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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]

Contents

Components

NameEC numberFunction
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

Glycine cleavage Glycine decarboxylase complex.svg
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. Glycine Serine catabolism.pdf
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

Related Research Articles

<span class="mw-page-title-main">Glycine</span> Amino acid

Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐CH2‐COOH. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (GGU, GGC, GGA, GGG). Glycine is integral to the formation of alpha-helices in secondary protein structure due to the "flexibility" caused by such a small R group. Glycine is also an inhibitory neurotransmitter – interference with its release within the spinal cord (such as during a Clostridium tetani infection) can cause spastic paralysis due to uninhibited muscle contraction.

Serine is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC.

Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carboxylation, the addition of CO2 to a compound. Enzymes that catalyze decarboxylations are called decarboxylases or, the more formal term, carboxy-lyases (EC number 4.1.1).

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Isocitrate dehydrogenase</span> Class of enzymes

Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.

<span class="mw-page-title-main">Glycine encephalopathy</span> Medical condition

Glycine encephalopathy is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebrospinal fluid.

<span class="mw-page-title-main">Oxaloacetate decarboxylase</span> Enzyme

Oxaloacetate decarboxylase is a carboxy-lyase involved in the conversion of oxaloacetate into pyruvate.

<span class="mw-page-title-main">Serine hydroxymethyltransferase</span>

Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) (Vitamin B6) dependent enzyme (EC 2.1.2.1) which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine and tetrahydrofolate (THF) to 5,10-Methylenetetrahydrofolate (5,10-CH2-THF). This reaction provides the largest part of the one-carbon units available to the cell.

<span class="mw-page-title-main">Serine dehydratase</span>

Serine dehydratase or L-serine ammonia lyase (SDH) is in the β-family of pyridoxal phosphate-dependent (PLP) enzymes. SDH is found widely in nature, but its structure and properties vary among species. SDH is found in yeast, bacteria, and the cytoplasm of mammalian hepatocytes. SDH catalyzes the deamination of L-serine to yield pyruvate, with the release of ammonia.

<span class="mw-page-title-main">Aminomethyltransferase</span> Protein-coding gene in the species Homo sapiens

Aminomethyltransferase is an enzyme that catabolizes the creation of methylenetetrahydrofolate. It is part of the glycine decarboxylase complex.

<span class="mw-page-title-main">Glycerate dehydrogenase</span>

In enzymology, a glycerate dehydrogenase (EC 1.1.1.29) is an enzyme that catalyzes the chemical reaction

Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP<sup>+</sup>) Enzyme

Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) (EC 1.1.1.40) or NADP-malic enzyme (NADP-ME) is an enzyme that catalyzes the chemical reaction in the presence of a bivalent metal ion:

<span class="mw-page-title-main">Glycine dehydrogenase (decarboxylating)</span> Protein-coding gene in the species Homo sapiens

Glycine decarboxylase also known as glycine cleavage system P protein or glycine dehydrogenase is an enzyme that in humans is encoded by the GLDC gene.

<span class="mw-page-title-main">Arginine decarboxylase</span>

The enzyme Acid-Induced Arginine Decarboxylase (AdiA), also commonly referred to as arginine decarboxylase, catalyzes the conversion of L-arginine into agmatine and carbon dioxide. The process consumes a proton in the decarboxylation and employs a pyridoxal-5'-phosphate (PLP) cofactor, similar to other enzymes involved in amino acid metabolism, such as ornithine decarboxylase and glutamine decarboxylase. It is found in bacteria and virus, though most research has so far focused on forms of the enzyme in bacteria. During the AdiA catalyzed decarboxylation of arginine, the necessary proton is consumed from the cell cytoplasm which helps to prevent the over-accumulation of protons inside the cell and serves to increase the intracellular pH. Arginine decarboxylase is part of an enzymatic system in Escherichia coli, Salmonella Typhimurium, and methane-producing bacteria Methanococcus jannaschii that makes these organisms acid resistant and allows them to survive under highly acidic medium.

<span class="mw-page-title-main">Aspartate 4-decarboxylase</span>

In enzymology, an aspartate 4-decarboxylase (EC 4.1.1.12) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase, is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Serine C-palmitoyltransferase</span>

In enzymology, a serine C-palmitoyltransferase (EC 2.3.1.50) is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">GCSH</span> Protein-coding gene in the species Homo sapiens

Glycine cleavage system H protein, mitochondrial is a protein that in humans is encoded by the GCSH gene. Degradation of glycine is brought about by the glycine cleavage system (GCS), which is composed of 4 protein components: P protein, H protein, T protein, and L protein. The H protein shuttles the methylamine group of glycine from the P protein to the T protein. The protein encoded by GCSH gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH). Two transcript variants, one protein-coding and the other probably not protein-coding, have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.

<span class="mw-page-title-main">Group I pyridoxal-dependent decarboxylases</span>

In molecular biology, the group I pyridoxal-dependent decarboxylases, also known as glycine cleavage system P-proteins, are a family of enzymes consisting of glycine cleavage system P-proteins EC 1.4.4.2 from bacterial, mammalian and plant sources. The P protein is part of the glycine decarboxylase multienzyme complex (GDC) also annotated as glycine cleavage system or glycine synthase. The P protein binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein. GDC consists of four proteins P, H, L and T.

Roland Douce was a plant biologist and professor who, along with his students, created a world-renowned plant biology centre in Grenoble, France, focusing on the biology of chloroplasts and mitochondria and their roles in plant metabolism under normal or stressed physiological conditions.

References

  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. S2CID   22516474.
  2. 1 2 3 4 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. Bibcode:2008PJAB...84..246K. doi:10.2183/pjab.84.246. PMC   3666648 . PMID   18941301.
  3. 1 2 3 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   43886 . 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. doi: 10.1016/S0021-9258(18)90562-4 . 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   1077305 . 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. doi: 10.1016/S0021-9258(20)82108-5 . 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. S2CID   10115240.
  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   2598024 . 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. S2CID   20224399.
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