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- Name help_outline guanidinoacetate Identifier CHEBI:57742 Charge 0 Formula C3H7N3O2 InChIKeyhelp_outline BPMFZUMJYQTVII-UHFFFAOYSA-N SMILEShelp_outline NC(=[NH2+])NCC([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 5 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline S-adenosyl-L-methionine Identifier CHEBI:59789 Charge 1 Formula C15H23N6O5S InChIKeyhelp_outline MEFKEPWMEQBLKI-AIRLBKTGSA-O SMILEShelp_outline C[S+](CC[C@H]([NH3+])C([O-])=O)C[C@H]1O[C@H]([C@H](O)[C@@H]1O)n1cnc2c(N)ncnc12 2D coordinates Mol file for the small molecule Search links Involved in 854 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline creatine Identifier CHEBI:57947 Charge 0 Formula C4H9N3O2 InChIKeyhelp_outline CVSVTCORWBXHQV-UHFFFAOYSA-N SMILEShelp_outline CN(CC([O-])=O)C(N)=[NH2+] 2D coordinates Mol file for the small molecule Search links Involved in 7 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,331 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline S-adenosyl-L-homocysteine Identifier CHEBI:57856 Charge 0 Formula C14H20N6O5S InChIKeyhelp_outline ZJUKTBDSGOFHSH-WFMPWKQPSA-N SMILEShelp_outline Nc1ncnc2n(cnc12)[C@@H]1O[C@H](CSCC[C@H]([NH3+])C([O-])=O)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 779 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:10656 | RHEA:10657 | RHEA:10658 | RHEA:10659 | |
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Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
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Publications
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Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase.
Komoto J., Huang Y., Takata Y., Yamada T., Konishi K., Ogawa H., Gomi T., Fujioka M., Takusagawa F.
Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis. The enzyme is found in abundance in the livers of all vertebrates. Recombinant rat liver GAMT has been crystallized with S-adenosylhomocysteine (SAH), and the crystal structure has been d ... >> More
Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis. The enzyme is found in abundance in the livers of all vertebrates. Recombinant rat liver GAMT has been crystallized with S-adenosylhomocysteine (SAH), and the crystal structure has been determined at 2.5 A resolution. The 36 amino acid residues at the N terminus were cleaved during the purification and the truncated enzyme was crystallized. The truncated enzyme forms a dimer, and each subunit contains one SAH molecule in the active site. Arg220 of the partner subunit forms a pair of hydrogen bonds with Asp134 at the guanidinoacetate-binding site. On the basis of the crystal structure, site-directed mutagenesis on Asp134, and chemical modification and limited proteolysis studies, we propose a catalytic mechanism of this enzyme. The truncated GAMT dimer structure can be seen as a ternary complex of protein arginine methyltransferase (one subunit) complexed with a protein substrate (the partner subunit) and the product SAH. Therefore, this structure provides insight into the structure and catalysis of protein arginine methyltransferases. << Less
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Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.
Stoeckler S., Isbrandt D., Hanefeld F., Schmidt B., von Figura K.
In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' ... >> More
In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine. << Less
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Catalytic mechanism of guanidinoacetate methyltransferase: crystal structures of guanidinoacetate methyltransferase ternary complexes.
Komoto J., Yamada T., Takata Y., Konishi K., Ogawa H., Gomi T., Fujioka M., Takusagawa F.
Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis. The enzyme is found in abundance in the livers of all vertebrates. The intact GAMT from recombinant rat liver has been crystallized with an inhibitor S-adenosylhomocysteine (SAH) and a su ... >> More
Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis. The enzyme is found in abundance in the livers of all vertebrates. The intact GAMT from recombinant rat liver has been crystallized with an inhibitor S-adenosylhomocysteine (SAH) and a substrate guanidinoacetate (GAA), and with SAH and an inhibitor guanidine (GUN). These ternary complex structures have been determined at 2.0 A resolution. GAMT has an alpha/beta open-sandwich structure, and the N-terminal section (residues 1-42) covers the active site entrance so that the active site is not visible. SAH has extensive interactions with GAMT through H-bonds and hydrophobic interactions. The guanidino groups of GAA and GUN form two pairs of H-bonds with E45 and D134, respectively. The carboxylate group of GAA interacts with the backbone amide groups of L170 and T171. A model structure of GAMT containing the two substrates (SAM and GAA) was built by attaching a methyl group (C(E)) on S(D) of the bound SAH. On the basis of this model structure, a catalytic mechanism of GAMT is proposed. The active site entrance is opened when the N-terminal section is moved out. GAA and SAM enter the active site and interact with the amino acid residues on the surface of the active site by polar and nonpolar interactions. O(D1) of D134 and C(E) of SAM approach N(E) of GAA from the tetrahedral directions. The O(D1)...N(E) and C(E)...N(E) distances are 2.9 and 2.2 A, respectively. It is proposed that three slightly negatively charged carbonyl oxygen atoms (O of T135, O of C168, and O(B) of GAA) around O(D1) of D134 increase the pK(a) of O(D1) so that O(D1) abstracts the proton on N(E). A strong nucleophile is generated on the deprotonated N(E) of GAA, which abstracts the methyl group (C(E)) from the positively charged S(D) of SAM, and creatine (methyl-GAA) and SAH (demethyl-SAM) are produced. E45, D134, and Y221 mutagenesis studies support the proposed mechanism. A mutagenesis study and the inhibitory mechanism of guanidine analogues support the proposed mechanism. << Less