Moderate Folate Depletion Increases Plasma Homocysteine and Decreases Lymphocyte DNA Methylation in Postmenopausal Women

Jacob, Robert A.; Gretz, Denise; Taylor, Peter; James, S. Jill; Pogribny, Igor P.; Miller, Barbara J.; Henning, Susanne M.; Swendseid, Marian E.

doi:10.1093/jn/128.7.1204

Cited by 439 publications

(285 citation statements)

References 31 publications

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“…It uses one-carbon units for the synthesis of purines and pyrimidines and sends one-carbon units to the methionine cycle for use in methylation reactions. Folate is a B vitamin and deficiency is known to be associated with neural tube defects [42], a decrease in DNA methylation [43], and the higher homocysteine levels that are biomarkers for cardio-vascular disease [44]. Folate deficiency and folate excess are associated with a variety of cancers [45,46].…”

Section: The Folate Cyclementioning

confidence: 99%

The biological significance of substrate inhibition: A mechanism with diverse functions

2010

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Many enzymes are inhibited by their own substrates, leading to velocity curves that rise to a maximum and then descend as the substrate concentration increases. Substrate inhibition is often regarded as a biochemical oddity and experimental annoyance. We show, using several case studies, that substrate inhibition often has important biological functions. In each case we discuss, the biological significance is different. Substrate inhibition of tyrosine hydroxylase results in a steady synthesis of dopamine despite large fluctuations in tyrosine due to meals. Substrate inhibition of acetylcholinesterase enhances the neural signal and allows rapid signal termination. Substrate inhibition of phosphofructokinase ensures that resources are not devoted to manufacturing ATP when it is plentiful. In folate metabolism, substrate inhibition maintains reactions rates in the face of substantial folate deprivation. Substrate inhibition of DNA methyltransferase serves to faithfully copy DNA methylation patterns when cells divide while preventing de novo methylation of methyl-free promoter regions. Keywords:.b iological function; enzyme kinetics; substrate inhibitionThe kinetics of an enzymatic reaction are typically studied by varying the concentration of substrate and plotting the rate of product formation as a function of substrate concentration. In the conventional case this yields a typical hyperbolic Michaelis-Menten curve, and a linear reciprocal LineweaverBurk plot, from which the kinetic constants of the enzyme can be calculated. A surprisingly large number of enzymes do not behave in this conventional way. Instead, their velocity curves rise to a maximum and then decline as the substrate concentration goes up. This phenomenon is referred to as substrate inhibition, and it is estimated that it occurs in some 20% of enzymes [1]. A partial list of enzymes that show substrate inhibition appears in Box 1.Substrate inhibition is often interpreted as an abnormality that comes from using artificially high substrate concentration in a laboratory setting. In a review article on the mechanisms of substrate inhibition in 1994, Kuehl [2] commented that ''although recognized early on as an almost universal phenomenon, it has nevertheless met an almost universal disinterest. Probably the main reason for this neglect is that the majority of enzymologists and many authorities in the field regard substrate inhibition as being almost always a nonphysiological phenomenon.'' There are several reasons for suspecting that substrate inhibition is not a pathological phenomenon, but a biologically relevant regulatory mechanism. First, in many cases normal substrate concentrations are to the right of the velocity maximum, which indicates that these enzymes typically operate under substrate inhibition. Second, many enzymes have specialized sites where a second substrate molecule can bind and act as an allosteric inhibitor. For those enzymes, substrate inhibition is clearly a specially evolved property. Third, evidence is accumulating that substr...

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Section: The Folate Cyclementioning

confidence: 99%

The biological significance of substrate inhibition: A mechanism with diverse functions

2010

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“…Moderate folate deficiency does not consistently induce global DNA hypomethylation in blood, liver and colon, despite a significant depletion in blood and tissue folate and liver SAM (52)(53)(54) . Lymphocyte DNA is hypomethylated in women made experimentally folate deficient over several weeks (55,56) and low-dietary folate intake (< 200 mg/d) correlates with hypomethylation of long-interspersed nucleotide element repeats (LINE-1; used as an indicator of global DNA methylation) in human colon tumours (57) . Conversely, LINE-1 methylation was not associated either with intake or blood folate in colon biopsy tissue collected from the Aspirin/Folate Polyp Prevention study (58) .…”

Section: Folate Deficiency Cancer and Cvd: A Common Mechanismmentioning

confidence: 99%

Epigenetic modifications and human pathologies: cancer and CVD

Duthie

2010

Proc. Nutr. Soc.

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Epigenetic changes are inherited alterations in DNA that affect gene expression and function without altering the DNA sequence. DNA methylation is one epigenetic process implicated in human disease that is influenced by diet. DNA methylation involves addition of a 1-C moiety to cytosine groups in DNA. Methylated genes are not transcribed or are transcribed at a reduced rate. Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumours. DNA hypomethylation, leading to increased expression of specific proto-oncogenes (e.g. genes involved in proliferation or metastasis) can increase the risk of cancer as can hypermethylation and reduced expression of tumour suppressor (TS) genes (e.g. DNA repair genes). DNA methyltransferases (DNMT), together with the methyl donor S-adenosylmethionine (SAM), facilitate DNA methylation. Abnormal DNA methylation is implicated not only in the development of human cancer but also in CVD. Polyphenols, a group of phytochemicals consumed in significant amounts in the human diet, effect risk of cancer. Flavonoids from tea, soft fruits and soya are potent inhibitors of DNMT in vitro, capable of reversing hypermethylation and reactivating TS genes. Folates, a group of water-soluble B vitamins found in high concentration in green leafy vegetables, regulate DNA methylation through their ability to generate SAM. People who habitually consume the lowest level of folate or with the lowest blood folate concentrations have a significantly increased risk of developing several cancers and CVD. This review describes how flavonoids and folates in the human diet alter DNA methylation and may modify the risk of human colon cancer and CVD.

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“…Huang et al 27 mostraram que ratos submetidos à baixa ingestão de folato apresentaram HHcy e maior susceptibilidade à danos causados pela peroxidação lipídica no fígado, além de comprometer a ação das enzimas antioxidantes de defesa hepática, sugerindo que elevados níveis de Hcy promovem peroxidação lipídica no fígado de ratos. Jacob et al 33 relatam que em humanos a baixa taxa de ingestão de folato resulta na elevação nos níveis de Hcy e de malonaldeído urinário (MDA).…”

Section: 2-homocisteína E Estresse Oxidativounclassified

Suplementação De Creatina, Homocisteína E Estresse Oxidativo

Deminice¹,

Vilhena²,

Portari³

et al. 2007

Medicina (Ribeirão Preto)

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Deminice R, Vilhena R, Portari GV, Jordão AA. Suplementação de creatina, homocisteína e estresse oxidativo.Medicina (Ribeirão Preto) 2007;40 (3): 368-77, jul./set. RESUMO:A creatina é uma substância popular entre atletas devido a sua possível propriedade ergogênica. Tal popularidade incentivou autores a estudar e explorar o possível potencial terapêutico desta substância. A síntese de creatina é responsável pela maioria das transferências de grupos metila no metabolismo hepático normal. Como a homocisteína é um aminoácido formado exclusivamente a partir da desmetilação da metionina, acredita-se que a creatina e homocisteína estejam metabolicamente conectadas. Estudos têm mostrado que a hiperhomocisteinemia está diretamente ligada à formação de espécies reativas de oxigênio pela autooxidação da homocisteína e/ou da cisteína e que tal auto-oxidação pode provocar danos celulares. O objetivo desta revisão é discutir aspectos da suplementação com creatina relacionados aos níveis de homocisteína e o estresse oxidativo.Descritores: Creatina. Suplementação Alimentar. Homocisteína. Estresse Oxidativo. 368Medicina, Ribeirão Preto, 2007; 40 (3): 368-77, jul./set. REVISÃO 1-INTRODUÇÃODevido aos seus possíveis efeitos no desempenho físico, a creatina (Cr) tornou-se um suplemento nutricional popular entre atletas principalmente a partir da década de 90. Recentemente, a creatina tem recebido considerável atenção na área médica. Alguns estudos têm mostrado efeitos benéficos da suplementação desta substância em pacientes ou modelos experimentais de diversas doenças como atrofia muscular, doenças cardiovasculares e neurodegenerativas 1,2,3 . Atualmente, alguma atenção tem sido dada para interação do metabolismo da homocisteína (Hcy) e da creatina e seu possível papel antioxidante 4,5 .Historicamente, autores que estudam a homocisteína, têm buscado entender as conseqüências de erros inatos sobre as enzimas que participam no metabolismo desse aminoácido e que resultam em hiperhomocisteinemia (HHcy) 6 . Ainda, alguns autores têm voltado sua atenção ao estado vitamínico 7,8 e polimorfismos genéticos relacionados à HHcy 9 . Recentemente, estudos têm buscado entender o balanço da demanda de metilação e os efeitos da modulação de tal balanço sobre o metabolismo da homocisteína 4,10,11 . Contudo, o objetivo desta revisão é discutir os efeitos da suplementação com creatina sobre os níveis de homocisteína, além do seu possível papel protetor contra a formação de espécies reativas de oxigênio, das interações e inter-relações da ingestão com a produção endógena de creatina.

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Moderate Folate Depletion Increases Plasma Homocysteine and Decreases Lymphocyte DNA Methylation in Postmenopausal Women

Cited by 439 publications

References 31 publications

The biological significance of substrate inhibition: A mechanism with diverse functions

The biological significance of substrate inhibition: A mechanism with diverse functions

Epigenetic modifications and human pathologies: cancer and CVD

Suplementação De Creatina, Homocisteína E Estresse Oxidativo

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