Abstract
Methionine (Met) is an essential amino acid that is needed for the synthesis of S-adenosylmethionine (AdoMet), the major biological methylating agent. Methionine used for AdoMet synthesis can be replenished via remethylation of homocysteine. Alternatively, homocysteine can be converted to cysteine via the transsulfuration pathway. Aberrations in methionine metabolism are associated with a number of complex diseases, including cancer, anemia, and neurodegenerative diseases. The concentration of methionine in blood and in organs is tightly regulated. Liver plays a key role in buffering blood methionine levels, and an interesting feature of its metabolism is that parallel tracks exist for the synthesis and utilization of AdoMet. To elucidate the molecular mechanism that controls metabolic fluxes in liver methionine metabolism, we have studied the dependencies of AdoMet concentration and methionine consumption rate on methionine concentration in native murine hepatocytes at physiologically relevant concentrations (40–400 µM). We find that both [AdoMet] and methionine consumption rates do not change gradually with an increase in [Met] but rise sharply (∼10-fold) in the narrow Met interval from 50 to 100 µM. Analysis of our experimental data using a mathematical model reveals that the sharp increase in [AdoMet] and the methionine consumption rate observed within the trigger zone are associated with metabolic switching from methionine conservation to disposal, regulated allosterically by switching between parallel pathways. This regulatory switch is triggered by [Met] and provides a mechanism for stabilization of methionine levels in blood over wide variations in dietary methionine intake.
Highlights
Methionine, an essential amino acid, plays a significant role in intracellular one-carbon and sulfur metabolism linking antioxidant and methylation homeostasis (Figure 1)
Methionine is an essential amino acid that is highly toxic at elevated levels, and the liver is primarily responsible for buffering its concentration in circulation
Methionine is needed for the synthesis of S-adenosylmethionine (AdoMet), the major biological methylating agent
Summary
Methionine, an essential amino acid, plays a significant role in intracellular one-carbon and sulfur metabolism linking antioxidant and methylation homeostasis (Figure 1). Since methionine is involved in many intracellular processes its levels in blood and in different organs need to be tightly regulated. Aberrations in methionine, and in methylation and antioxidant metabolism, are associated with a number of complex diseases, including cancer, anemia, neurodegenerative diseases, and developmental abnormalities [4,5]. Elucidating the multiple switches that regulate methionine metabolism is key to understanding their dysregulation. Such information may permit intervention that would reverse disease states
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