Mathematical models of folate-mediated one-carbon metabolism.

Folate-mediated one-carbon metabolism is an unusually complex metabolic network, consisting of several interlocking cycles, and compartmentation between cytosol and mitochondria. The cycles have diverse functions, the primary being thymidylate synthesis (the rate limiting step in DNA synthesis), the initial steps in purine synthesis, glutathione synthesis, and a host of methyl transfer reactions that include DNA and histone methylation. Regulation within the network is accomplished by numerous allosteric interactions in which metabolites in one part of the network affect the activity of enzymes elsewhere in the network. Although a large body of experimental work has elucidated the details of the mechanisms in every part of the network, the multitude of complex and non-linear interactions within the network makes it difficult to deduce how the network as a whole operates. Understanding the operation of this network is further complicated by the fact that human populations maintain functional polymorphisms for several enzymes in the network, and that the network is subject to continual short and long-term fluctuations in its inputs as well as in demands on its various outputs. Understanding how such a complex system operates is possible only by means of mathematical models that take account of all the reactions and interactions. Simulations with such models can be used as an adjunct to laboratory experimentation to test ideas and alternative hypotheses and interpretations quickly and inexpensively. A number of mathematical models have been developed over the years, largely motivated by the need to understand the complex mechanisms by which anticancer drugs like methotrexate inhibit nucleotide synthesis and thus limit the ability of cells to divide. More recently, mathematical models have been used to investigate the regulatory and homeostatic mechanisms that allow the system to accommodate large fluctuations in one part of the network without affecting critical functions elsewhere in the network.