Disease relevance of Gamt

• Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency [1].
• However, when acutely stressed by inotropic stimulation or ischemia/reperfusion, GAMT-/- mice exhibit a markedly abnormal phenotype, demonstrating that an intact, high-capacity CK/PCr system is required for situations of increased cardiac work or acute stress [2].
• CONCLUSIONS: GAMT-/- mice do not develop hypertrophy and show normal cardiac function at low workload, suggesting that a fully functional CK/PCr system is not essential under resting conditions [2].
• METHODS AND RESULTS: GAMT-/- mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and beta-myosin heavy chain) [2].

High impact information on Gamt

• We generated a knockout mouse model for guanidinoacetate N-methyltransferase (GAMT) deficiency (MIM 601240), the first discovered human creatine deficiency syndrome, by gene targeting in embryonic stem cells [1].
• Data presented in this report show that S-adenosylmethionine and methionine accumulate abnormally in the plasma of humans with glycine N-methyltransferase deficiency but not of those with guanidinoacetate N-methyltransferase deficiency or in the plasma or livers of mice devoid of phosphatidylethanolamine N-methyltransferase activity [3].
• The available evidence indicates that the quantitatively most important pathways for S-adenosylmethionine-dependent transmethylation in mammals are the syntheses of creatine by guanidinoacetate methyltransferase, of phosphatidylcholine by phosphatidylethanolamine methyltransferase, and of sarcosine by glycine N-methyltransferase [3].
• Phosphorylated guanidinoacetate partly compensates for the lack of phosphocreatine in skeletal muscle of mice lacking guanidinoacetate methyltransferase [4].
• (31)P MR spectra of hindleg muscle of GAMT-deficient (GAMT-/-) mice showed no phosphocreatine (PCr) signal and instead showed the signal for phosphorylated guanidinoacetate (PGua), the immediate precursor of Cr, which is not normally present [4].

Chemical compound and disease context of Gamt

• Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice [2].

Biological context of Gamt

• The gene encoding guanidinoacetate methyltransferase (GAMT) maps to human chromosome 19 at band p13.3 and to mouse chromosome 10 [5].
• Cr supplementation for 2 days in GAMT-/- animals (GAMT(Cr)-/-) resulted in normalization to Con values for relaxation times, relative force at lower stimulation frequencies, and relative force during 30 isometric contractions [6].
• To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT-/- mice [2].

Anatomical context of Gamt

• Furthermore, as the male mouse developed from neonatal stages through sexual maturity, the GAMT protein level increased in testis but decreased in liver [7].
• The results show that GAMT was regulated at tissue-specific levels; the enzyme was most highly expressed in testis, caput epididymis, ovary, and liver [7].
• Guanidinoacetate methyltransferase in the mouse: extensive expression in Sertoli cells of testis and in microvilli of caput epididymis [7].
• As a means for determining why the testis and seminal vesicles contain high levels of Cr, we analyzed GAMT protein and mRNA levels in mouse tissues by Western and Northern blot analyses [7].
• These results indicate that Cr is synthesized extensively in the epithelia of seminiferous tubules and caput epididymis, suggesting that GAMT or metabolic pathways related to Cr biosynthesis may be important for germ cell development or function [7].

Associations of Gamt with chemical compounds

• Our results show that despite the absence of Cr, GAMT-/- mice can cope with mild ischaemic stress by using PGua for high energy phosphoryl transfer [4].
• Guanidinoacetate methyltransferase (GAMT) catalyzes the last step of the biosynthetic pathway to creatine (Cr), the transfer of a methyl group from S-adenosylmethionine to guanidinoactate [7].
• However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT-/- hearts (101+/-8 mm Hg in WT versus 59+/-7 mm Hg in GAMT-/-; P<0.05) [2].

Analytical, diagnostic and therapeutic context of Gamt

• Lower force and impaired performance during high-intensity electrical stimulation in skeletal muscle of GAMT-deficient knockout mice [6].
• MR spectroscopy of muscle and brain in guanidinoacetate methyltransferase (GAMT)-deficient mice: validation of an animal model to study creatine deficiency [8].

References