Traumatic Brain Injury Alters Methionine Metabolism: Implications for Pathophysiology

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.

Severity of experimental traumatic brain injury modulates changes in concentrations of cerebral free amino acids

“…On the other hand, a Cys decrease may negatively influence the rate of GSH biosynthesis, thereby contributing to the previously observed decrease in GSH content as a consequence of marked oxidative stress occurring after sTBI [34]. It was recently reported that groups of mTBI and sTBI patients had decreased levels of circulating Met and SAM, much more evident in sTBI than in mTBI patients, thus confirming the existence of an altered methyl-cycle after a traumatic insult [73].…”

Antioxidant Therapies in Traumatic Brain Injury

“…Whilst in mild TBI (mTBI), a spontaneous recovery late post-injury was observed, severely injured animals had a permanent decrease of brain GSH up to a week following TBI [56]. In addition, a decrease of GSH in CSF of children who suffered a severe TBI has also been reported [73]. Similarly, lower levels of cysteine and glycine, both fundamental for the GSH biosynthesis, were also demonstrated after mild and severe TBI [74].…”

Blood Metabolites Associate with Prognosis in Endometrial Cancer

“…Important intermediates include one-carbon metabolites, S-adenosylmethionine (SAM), and several metabolites which are involved in glycolysis and the TCA cycle. SAM is a methyldonor involved in epigenetic changes in gene expression, which is generated from the transmethylation pathway from the metabolism of methionine [46]. Moreover, SAM is involved in the synthesis of phosphatidylcholine.…”