A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

Salcedo-Sora, J. Enrique; Auley, Mark T. Mc

doi:10.1039/c5mb00801h

Cited by 15 publications

(7 citation statements)

References 65 publications

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“…The essence of this approach is to utilise novel approaches to study molecules, cells or entire organisms. Nutrition research is no different and is beginning to benefit from this new paradigm (74)(75)(76)(77)(78)(79)(80) . It can be argued that electrochemical techniques come under this umbrella of systems techniques.…”

Section: Detecting Dna Methylationmentioning

confidence: 99%

The role of DNA methylation in ageing and cancer

2018

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The aim of the present review paper is to survey the literature related to DNA methylation, and its association with cancer and ageing. The review will outline the key factors, including diet, which modulate DNA methylation. Our rationale for conducting this review is that ageing and diseases, including cancer, are often accompanied by aberrant DNA methylation, a key epigenetic process, which is crucial to the regulation of gene expression. Significantly, it has been observed that with age and certain disease states, DNA methylation status can become disrupted. For instance, a broad array of cancers are associated with promoter-specific hypermethylation and concomitant gene silencing. This review highlights that hypermethylation, and gene silencing, of the EN1 gene promoter, a crucial homeobox gene, has been detected in various forms of cancer. This has led to this region being proposed as a potential biomarker for diseases such as cancer. We conclude the review by describing a recently developed novel electrochemical method that can be used to quantify the level of methylation within the EN1 promoter and emphasise the growing trend in the use of electrochemical techniques for the detection of aberrant DNA methylation.

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Section: Detecting Dna Methylationmentioning

confidence: 99%

The role of DNA methylation in ageing and cancer

2018

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“…The systems biology paradigm contrasts with the more traditional reductionist approach, commonly used in nutrition research, and offers a more integrated way to study this multifaceted system (14,113,114) . A fundamental element of this paradigm shift is the close coupling of computational modelling with experimental work (115)(116)(117)(118) . Our group has used computational systems biology to investigate cholesterol metabolism and ageing (119) .…”

Section: Applying Systems Biology To Our Understanding Of Cholesterolmentioning

confidence: 99%

Investigating cholesterol metabolism and ageing using a systems biology approach

et al. 2016

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CVD accounted for 27 % of all deaths in the UK in 2014, and was responsible for 1·7 million hospital admissions in 2013/2014. This condition becomes increasingly prevalent with age, affecting 34·1 and 29·8 % of males and females over 75 years of age respectively in 2011. The dysregulation of cholesterol metabolism with age, often observed as a rise in LDL-cholesterol, has been associated with the pathogenesis of CVD. To compound this problem, it is estimated by 2050, 22 % of the world's population will be over 60 years of age, in culmination with a growing resistance and intolerance to pre-existing cholesterol regulating drugs such as statins. Therefore, it is apparent research into additional therapies for hypercholesterolaemia and CVD prevention is a growing necessity. However, it is also imperative to recognise this complex biological system cannot be studied using a reductionist approach; rather its biological uniqueness necessitates a more integrated methodology, such as that offered by systems biology. In this review, we firstly discuss cholesterol metabolism and how it is affected by diet and the ageing process. Next, we describe therapeutic strategies for hypercholesterolaemia, and finally how the systems biology paradigm can be utilised to investigate how ageing interacts with complex systems such as cholesterol metabolism. We conclude by emphasising the need for nutritionists to work in parallel with the systems biology community, to develop novel approaches to studying cholesterol metabolism and its interaction with ageing.

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“…Moreover, this model showed that oxidative stress increases the plasma SAM/S-SAM/SAH ratio. The most recent ODE model of folate metabolism was developed by Salcedo-Sora and Mc Auley (2016) [67]. Our model is the first computational model of microbial folate biosynthesis and utilization.…”

Section: Computational Models Of Folate Metabolismmentioning

confidence: 99%

“…Therefore, it is extremely unlikely that a mathematical model can be assembled from one biological source. This is highlighted by our recent model of microbial folate metabolism, where the parameters were derived from a number of sources [67]. It is also a feature of the mammalian computational models, which have previously relied on data from rat, mice and human studies [61].…”

Section: Theoretical Framework and Obstacles To Creating A Combined mentioning

confidence: 99%

“…Rate laws for more complex reaction laws are in general described by Michaelis-Menten kinetics [85] for one, two or three substrates assuming a random-order mechanism. The following mathematical expressions taken from the recent model by Salcedo-Sora and Mc Auley (2016) [67] encapsulate the different Michaelis-Menten-based functional forms as used for one, two and three substrates in these types of kinetic models, where V is the velocity of the reaction, V max , is the theoretical maximum velocity of the reaction, S1-S3 are substrates and k m1 -k m3 are the substrate concentrations at which the reaction is half maximum velocity.…”

Section: Computational Models Of Folate Metabolismmentioning

confidence: 99%

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Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

2016

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Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.

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A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

Cited by 15 publications

References 65 publications

The role of DNA methylation in ageing and cancer

The role of DNA methylation in ageing and cancer

Investigating cholesterol metabolism and ageing using a systems biology approach

Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

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