Influence of phenylketonuria's diet on dimethylated arginines and methylation cycle

Abstract

Phenylketonuria's (PKU) treatment based on low natural protein diet may affect homocysteine (Hcys) metabolic pathway. Hcys alteration may be related to the methylation of arginine to asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which both modify nitric oxide production. The aim of this work is to evaluate the status of Hcys formation methylation cycle and ADMA and SDMA levels in patients with PKU in order to establish a potential relationship.Forty-two early diagnosed PKU patients under dietary treatment and good adherence to their diets were enrolled in this cross-sectional study. Their nutritional and biochemical profile, as well as Hcys synthesis status, ADMA and SDMA levels were analyzed and compared with a control group of 40 healthy volunteers. ADMA and SDMA were determined by high-performance liquid chromatography system coupled to triple quadrupole mass spectrometer.In this study, 23 classic PKU, 16 moderate PKU, and 3 mild HPA were enrolled. The median age was 10 years old. Median ADMA, SDMA, and Hcys concentration levels (5.1 μM [2.3-25.7], 0.35 μM [0.18-0.57], 0.43 μM [0.26-0.61], respectively) were lower in patients with PKU (P < .001 for ADMA and SDMA) whereas vitamin B12 and folate levels (616 pg/mL [218-1943] and 21 ng/mL [5-51], respectively) were higher comparing with controls. Statistically significant correlations were found between ADMA, and Phe (r = -0.504, P = .001) and Hcys (r = -0.458, P = .037) levels. Several nutrition biomarkers, such as prealbumin, 25-hydroxy vitamin D, selenium, and zinc, were below the normal range.Our study suggests that patients with PKU suffer from poor methylation capacity. Restriction of natural proteins in addition to high intake of vitamin B12 and folic acid supplementation in the dietary products, produce an impairment of methylation cycle that leads to low Hcys and ADMA levels. As a result, methylated compounds compete for methyl groups, and there is an impairment of methylation cycle due to low Hcys levels, which is related to the lack of protein quality, despite of elevated concentrations of cofactors.

Figure 1

Methylation cycle pathway: (A) Methionine and homocysteine (Hcys) are generated by the following enzymes: CBS = cystathionine β-synthase, MAT = methionine adenosyltransferase, MS = methionine synthase, SAHH = S-adenosylhomocysteine hydrolasa. (B) Asymmetric dimethylarginine (ADMA) synthesis catalyzed by protein arginine methyltransferases (PRMT) and proteinases, and its involvement in the inhibition of nitric oxide by competition with nitric oxide synthase (NOS) for arginine. ADMA is degraded to citrulline and amines by dimethylarginine dimethylamino hydrolase (DDAH). (C) Relationship between the metabolic pathway from arginine to creatine, where guanidinoacetate acts as a methyl acceptor, and the methylation cycle. AGAT = l-arginine: glycine amidinotransferase, GAMT = guanidinoacetate N-methyltransferase.

Figure 2

Plasma levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in patients with PKU comparing with the control group.

Figure 3

Correlation between asymmetric Phe (μM) and Hcys (μM) levels by linear regression (corrected r² = 0.265, P = .017).

Figure 4

Correlation between Phe (μM) and ADMA (μM) levels by linear regression (corrected r² = 0.302, P < .001).