Abstract
Methionine is an essential proteinogenic amino acid that is obtained from the diet. In addition to its requirement for protein biosynthesis, methionine is metabolized to generate metabolites that play key roles in a number of cellular functions. Metabolism of methionine via the transmethylation pathway generates S-adenosylmethionine (SAM) that serves as the principal methyl (−CH3) donor for DNA and histone methyltransferases (MTs) to regulate epigenetic changes in gene expression. SAM is also required for methylation of other cellular proteins that serve various functions and phosphatidylcholine synthesis that participate in cellular signaling. Under conditions of oxidative stress, homocysteine (which is derived from SAM) enters the transsulfuration pathway to generate glutathione, an important cytoprotective molecule against oxidative damage. As both experimental and clinical studies have shown that traumatic brain injury (TBI) alters DNA and histone methylation and causes oxidative stress, we examined if TBI alters the plasma levels of methionine and its metabolites in human patients. Blood samples were collected from healthy volunteers (HV; n = 20) and patients with mild TBI (mTBI; GCS > 12; n = 20) or severe TBI (sTBI; GCS < 8; n = 20) within the first 24 h of injury. The levels of methionine and its metabolites in the plasma samples were analyzed by either liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry (LC-MS or GC-MS). sTBI decreased the levels of methionine, SAM, betaine and 2-methylglycine as compared to HV, indicating a decrease in metabolism through the transmethylation cycle. In addition, precursors for the generation of glutathione, cysteine and glycine were also found to be decreased as were intermediate metabolites of the gamma-glutamyl cycle (gamma-glutamyl amino acids and 5-oxoproline). mTBI also decreased the levels of methionine, α-ketobutyrate, 2 hydroxybutyrate and glycine, albeit to lesser degrees than detected in the sTBI group. Taken together, these results suggest that decreased levels of methionine and its metabolic products are likely to alter cellular function in multiple organs at a systems level.
Highlights
It has been appreciated for more than 30 years that the resting metabolic expenditure of the severely injured brain is almost 40% higher than that of the non-injured brain, and is associated with a negative nitrogen balance, suggesting increased protein catabolism (Clifton et al, 1985)
Post hoc analysis revealed a significant reduction of plasma methionine in both mild and severe traumatic brain injury (TBI) patients relative to healthy volunteers (HV), with greater reductions detected in the sTBI group (Figure 1B)
Our measurements of methionine and its metabolites in plasma samples from sTBI, mild TBI (mTBI), and HV revealed four key findings: (1) the relative plasma levels of methionine and SAM are significantly reduced in sTBI patients; (2) the levels of cysteine and glycine, the precursors for the synthesis of glutathione, are reduced in sTBI patients; (3) in contrast to that observed in sTBI patients, the plasma levels of cysteine were significantly elevated in mTBI; and (4) the relative levels of several gamma-glutamyl amino acids and 5-oxoproline are significantly reduced in the plasma of sTBI patients
Summary
It has been appreciated for more than 30 years that the resting metabolic expenditure of the severely injured brain is almost 40% higher than that of the non-injured brain, and is associated with a negative nitrogen balance (the difference between nitrogen uptake and nitrogen excretion), suggesting increased protein catabolism (Clifton et al, 1985). The transmethylation pathway generates S-adenosylmethionine (SAM), an important methyl donor for the methylation of lipids, proteins, and nucleotides. In addition to generating SAM, methionine is required for the synthesis of glutathione via the transsulfuration pathway. Cells use glutathione to scavenge reactive oxygen species (ROS) in order to reduce oxidative damage. Both experimental and clinical studies have shown that TBI causes oxidative damage to the injured brain, which may be related to decreases in glutathione availability (Povlishock and Kontos, 1992; Bayir et al, 2002; Singh et al, 2006; Bains and Hall, 2012). Decreases in the levels of methionine and/or its metabolic products may underlie oxidative damage and the progression of TBI pathology and outcome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
