Allen R H, Stabler S P, Lindenbaum J
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Metabolism. 1993 Nov;42(11):1448-60. doi: 10.1016/0026-0495(93)90198-w.
Homocysteine and 5-CH3-tetrahydrofolate (5-CH3-THF) are converted to methionine and THF by the CH3-cobalamin (CH3-Cbl)-dependent enzyme methionine synthase. Serum homocysteine levels are elevated in more than 95% of patients with Cbl or folate deficiency and in patients with inborn errors involving the synthesis of 5-CH3-THF or CH3-Cbl. Homocysteine and betaine are converted to methionine and N,N-dimethylglycine by betaine-homocysteine methyltransferase. It requires neither Cbl nor folate, although N,N-dimethylglycine is converted to N-methylglycine and then to glycine in reactions that both involve the formation of 5,10-CH2-THF from THF. Large amounts of betaine are often given orally to patients with inborn errors, even though little is known about its metabolism in normal subjects or these patients. Thus we developed new gas chromatographic-mass spectrometric assays for serum betaine, N,N-dimethylglycine, and N-methylglycine. In 60 blood donors, we found ranges for normal serum of 17.6 to 73.3, 1.42 to 5.27, and 0.60 to 2.67 mumol/L for the three metabolites, respectively, which were normal in the majority of 50 patients with Cbl deficiency, none of whom had increased levels of N-methylglycine. In 25 patients with folate deficiency, serum betaine level was normal in most, but 76% and 60% had elevations of N,N-dimethylglycine and N-methylglycine levels that ranged as high as 343 and 43.2 mumol/L, respectively. All of seven patients on betaine therapy for inborn errors had high values for betaine (167 to 3,900 mumol/L), N,N-dimethylglycine (15.1 to 250 mumol/L), and N-methylglycine (2.93 to 49.3 mumol/L). Serum total homocysteine levels remained very high at 47.2 to 156 mumol/L (normal, 5.4 to 16.2). In patients with cbl C and cbl D mutations, methionine levels remained low or low-normal at 8.3 to 15.6 mumol/L (normal, 13.3 to 42.7) despite betaine treatment. We conclude that (1) betaine levels are maintained in most patients with Cbl and folate deficiency; (2) levels of N,N-dimethylglycine and N-methylglycine are increased in most patients with folate deficiency; and (3) betaine therapy is relatively ineffective in patients with defective synthesis of CH3-Cbl.
同型半胱氨酸和5-甲基四氢叶酸（5-CH3-THF）通过依赖于甲基钴胺素（CH3-Cbl）的蛋氨酸合酶转化为蛋氨酸和四氢叶酸（THF）。超过95%的钴胺素或叶酸缺乏患者以及患有涉及5-CH3-THF或CH3-Cbl合成的先天性代谢缺陷的患者，其血清同型半胱氨酸水平会升高。同型半胱氨酸和甜菜碱通过甜菜碱-同型半胱氨酸甲基转移酶转化为蛋氨酸和N，N-二甲基甘氨酸。该反应既不需要钴胺素也不需要叶酸，不过N，N-二甲基甘氨酸会在涉及从THF形成5，10-亚甲基四氢叶酸的反应中依次转化为N-甲基甘氨酸，然后再转化为甘氨酸。尽管对甜菜碱在正常受试者或这些患者体内的代谢了解甚少，但仍经常给患有先天性代谢缺陷的患者口服大量甜菜碱。因此，我们开发了用于检测血清甜菜碱、N，N-二甲基甘氨酸和N-甲基甘氨酸的新型气相色谱-质谱分析法。在60名献血者中，我们发现这三种代谢物在正常血清中的浓度范围分别为17.6至73.3、1.42至5.27和0.60至2.67μmol/L，50名钴胺素缺乏患者中的大多数人这些指标正常，其中无人N-甲基甘氨酸水平升高。在25名叶酸缺乏患者中，大多数人的血清甜菜碱水平正常，但76%和60%的患者N，N-二甲基甘氨酸和N-甲基甘氨酸水平升高，分别高达343和43.2μmol/L。所有接受甜菜碱治疗的7名先天性代谢缺陷患者的甜菜碱（167至3900μmol/L）、N，N-二甲基甘氨酸（15.1至250μmol/L）和N-甲基甘氨酸（2.93至49.3μmol/L）值均较高。血清总同型半胱氨酸水平仍非常高，为47.2至156μmol/L（正常范围为5.4至16.2）。在患有cbl C和cbl D突变的患者中，尽管接受了甜菜碱治疗，但蛋氨酸水平仍维持在较低或略低于正常的水平，为8.3至15.6μmol/L（正常范围为13.3至42.7）。我们得出结论：（1）大多数钴胺素和叶酸缺乏患者的甜菜碱水平保持正常；（2）大多数叶酸缺乏患者的N，N-二甲基甘氨酸和N-甲基甘氨酸水平升高；（3）甜菜碱治疗对CH3-Cbl合成缺陷的患者相对无效。
