McBreairty Laura E
Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL A1B 3X9, Canada.
Appl Physiol Nutr Metab. 2016 Jun;41(6):691. doi: 10.1139/apnm-2016-0158. Epub 2016 May 20.
Methionine is an essential amino acid which when not incorporated into protein, can be converted to S-adenosylmethionine, the universal methyl donor in over 200 transmethylation reactions, which include creatine and phosphatidylcholine (PC) synthesis, as well as deoxyribonucleic acid (DNA) methylation. Following transmethylation, homocysteine is formed, which can be converted to cysteine via transsulfuration or remethylated to methionine by receiving a methyl group from folate or betaine. Changes to methyl group availability in utero can lead to permanent changes in epigenetic patterns of DNA methylation, which has been implicated in "fetal programming", a phenomenon associated with poor nutrition during fetal development that results in low birth weight and disease in later life. It has been shown that programming can also occur in the neonate. Our global objective was to understand how the variability of nutrients involved in methionine metabolism can affect methionine and methyl group availability. We hypothesize that nutrients that converge on methionine metabolism can affect methionine availability for its various functions. In this thesis, we used intrauterine growth restricted (IUGR) piglets to investigate whether a global nutritional insult in utero can lead to a perturbed methionine metabolism. Our results demonstrate that IUGR piglets have a lower capacity to dispose of homocysteine via both transsulfuration and remethylation pathways, as well as a lower incorporation of methyl groups into PC. The second objective of this thesis was to determine whether variation in methionine supply and demand can affect methionine availability. We demonstrated that stimulating either acute or chronic creatine synthesis leads to lower methyl incorporation into protein and PC in pigs. Furthermore, when methionine is limiting, supplementation with either folate or betaine leads to higher methionine availability for protein synthesis. Finally, because creatine is increasingly being utilized as an ergogenic and neuroprotective supplement, we wanted to determine whether provision of the creatine precursor, guanidinoacetate (GAA), could effectively increase tissue creatine stores. We showed that 2.5 weeks of supplementation with GAA is more effective than creatine at increasing hepatic and muscle creatine stores. The results of this thesis demonstrate that the presence of IUGR, an increased demand for creatine synthesis, or the supplementation with remethylation nutrients can each affect methionine availability; all are important when considering neonatal nutrient requirements. Furthermore, although GAA is effective at increasing levels of tissue creatine, higher GAA methylation can limit methionine availability for growth and synthesis of PC.
蛋氨酸是一种必需氨基酸，当它未被整合到蛋白质中时，可转化为S-腺苷甲硫氨酸，这是200多种转甲基反应中的通用甲基供体，这些反应包括肌酸和磷脂酰胆碱（PC）的合成以及脱氧核糖核酸（DNA）甲基化。转甲基作用后，会形成同型半胱氨酸，它可以通过转硫作用转化为半胱氨酸，或者通过从叶酸或甜菜碱接受一个甲基再甲基化生成蛋氨酸。子宫内甲基基团可用性的变化会导致DNA甲基化表观遗传模式的永久性改变，这与“胎儿编程”有关，“胎儿编程”是一种与胎儿发育期间营养不良相关的现象，会导致低出生体重和日后的疾病。研究表明，这种编程也可能发生在新生儿身上。我们的总体目标是了解参与蛋氨酸代谢的营养素变异性如何影响蛋氨酸和甲基基团的可用性。我们假设汇聚于蛋氨酸代谢的营养素会影响蛋氨酸用于其各种功能的可用性。在本论文中，我们使用宫内生长受限（IUGR）仔猪来研究子宫内的整体营养损伤是否会导致蛋氨酸代谢紊乱。我们的结果表明，IUGR仔猪通过转硫和再甲基化途径处理同型半胱氨酸的能力较低，并且甲基基团掺入PC的量也较低。本论文的第二个目标是确定蛋氨酸供需变化是否会影响蛋氨酸的可用性。我们证明，刺激急性或慢性肌酸合成会导致猪体内甲基掺入蛋白质和PC的量降低。此外，当蛋氨酸受到限制时，补充叶酸或甜菜碱会使蛋白质合成中蛋氨酸的可用性更高。最后，由于肌酸越来越多地被用作一种提高运动能力和神经保护的补充剂，我们想确定提供肌酸前体胍基乙酸（GAA）是否能有效增加组织肌酸储备。我们表明，补充2.5周的GAA在增加肝脏和肌肉肌酸储备方面比补充肌酸更有效。本论文的结果表明，IUGR的存在、对肌酸合成需求的增加或补充再甲基化营养素都会影响蛋氨酸的可用性；在考虑新生儿营养需求时，所有这些都很重要。此外，尽管GAA在提高组织肌酸水平方面有效，但较高的GAA甲基化会限制蛋氨酸用于生长和PC合成的可用性。
