Creatine synthesis

Arginine is the formamidine donor for creatine synthesis (Figure 31-6) and via ornithine to putrescine, spermine, and spermidine (Figure 31-3) Arginine is also the precursor of the intercellular signaling molecule ni-... 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Stockier S, Marescau B, De Deyn PP, Trijbels JM, Hanefeld F (1997) Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis. Metabolism 46 1189-11939... 

D. Valine is an essential amino acid and is not synthesized in the human. Glydne reacts with sucdnyl CoA in the first step of heme synthesis and with arginine in the first step of creatine synthesis. The entire glycine molecule is incorporated into the growing purine ring. 

Myotonic dystrophy appears as a rather special case, since creatinuria is small or absent. In this disease it is thought that there is also a decrease in creatine synthesis, possibly due to an endocrine disturbance (see Zl). There is some indication that the same may be true of the hereditary myopathy in mice (P16). 

These reactions occur in liver, kidney, and pancreas, from which creatine is transported to organs such as muscle and brain. Creatine synthesis is subject to negative modulation of amidinotransferase by creatine. Phosphocreatine production is catalyzed by creatine kinase ... 

Creatine synthesis. The synthesis of creatine, including the major control, is depicted above. The tissue where the reaction occurs is indicated in parenthesis in purple. The formation of creatinine from creatine phosphate is also shown. (See text for more detail.)... 

Creatine synthesis is well controlled. The control occurs at the transamidinase step in the kidney. If creatine is fed, a marked decrease in the amount of the transamidinase occurs. Thus, excess production of creatine is avoided. If creatinine is fed, there is no effect on the transamidinase, because creatinine is only an end product and will be excreted. 

S-Adenosylmethionine is the specific methyl donor in reactions catalyzed by two partially purified enzymes one makes iV-methylnico-tinamide and the other creatine (IX). These reactions proceed to completion, and no evidence for reversal has been found. The other reaction product in the case of creatine synthesis has been identified as adenosylhomocysteine. ... 

Findings compatible with defect in creatine synthesis (see text)... 

Fig. 12.3. Diagnostic policy for hyperornithinemia (HOGA) starting points are clinical symptoms and/or the finding of hyperornithinemiaZ-ornithinuria. Findings compatible with defect in creatine synthesis DD, differential diagnosis...

According to the creatine pathways in the body, two main categories of disorders in creatine metabolism can be expected disorders in creatine synthesis, and disorders of cellular creatine transport. 

According to the limited number of patients identified so far, the clinical spectrum of GAMT, AGAT and CRTR deficiencies includes mental retardation as main symptom. Further recognition of patients with defects in creatine synthesis will be of major importance as affected patients may substantially benefit from oral creatine substitution. Determination of guanidinoacetate, creatine and creatinine in body fluids and determination of brain creatine by in vivo magnetic resonance spectroscopy are valuable diagnostic tools. 

Van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, Powels PJW, Onkenhout W, Peeters EA, Stockler-Ipsiroglu S, Jakobs C. Mental retardation and behavioural problems as presenting signs in a creatine synthesis defect. Ann Neurol 2000 47 540-543... 

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