Homocysteine and Alzheimer's disease

Morris, Martha Savaria

doi:10.1016/s1474-4422(03)00438-1

Cited by 336 publications

(213 citation statements)

References 29 publications

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“…The maintenance of low homocysteine concentrations is essential not only for a proper flow of sulfur in the transsulfuration pathway and the methionine cycle, but also for evading toxic effects of the molecule, which has been implicated in pathological conditions associated with various genetic disorders causing homocystinuria and homocysteinemia (2). Homocysteine has also been shown to be the pro-oxidant causing damage to the vascular endothelia (3), and associated with an increased cardiovascular risk (4) and Alzheimer's disease (5).…”

Section: Introductionmentioning

confidence: 99%

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Sato

Nozaki

2009

IUBMB Life

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SummarySulfur-containing amino acids (SAAs) are essential components in many biological processes and ubiquitously distributed to all organisms. Both biosynthetic and catabolic pathways of SAAs are heterogeneous among organisms and between developmental stages, and regulated by the environmental changes. Limited lineage of organisms ranging from archaea to plants, but not human, possess a unique enzyme methionine gammalyase (MGL, EC 4.4.1.11) to directly degrade SAA to a-keto acids, ammonia, and volatile thiols. The reaction mechanisms and the physiological roles of this enzyme are partially demonstrated by the enzymological analyzes, structure determination, isotopic labeling of the intermediate metabolites, and functional analyzes of deficient mutants. MGL has been exploited as a drug target for the infectious diseases caused by parasitic protozoa and anaerobic periodontal bacteria. In addition, MGL has been utilized to develop therapeutic interventions of various cancers, by introducing recombinant proteins to deplete methionine essential for the growth of cancer cells. In this review, we discuss the current understanding of enzymological properties, putative physiological roles, and therapeutic applications of MGL.

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Section: Introductionmentioning

confidence: 99%

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Sato

Nozaki

2009

IUBMB Life

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“…Hyperhomocysteinemia is a an emerging risk factor for carotid artery disease (atherosclerosis) and stroke and is associated with Alzheimer's disease and vascular dementia. [7][8][9][10][11] It was not until relatively recently, however, that experimental studies began to define the impact of hyperhomocysteinemia on cerebral vascular biology and the molecular mechanisms that account for these changes. This work has been facilitated by the development of mouse models with genetic alterations in different components of the homocysteine metabolic pathway (see below).…”

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confidence: 99%

Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction

Faraci

Lentz

2004

Stroke

209

147

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A n elevated circulating concentration of the sulfurcontaining amino acid homocysteine, hyperhomocysteinemia, produces complex changes within the blood vessel wall. In the peripheral circulation, these changes include oxidative stress, proinflammatory effects such as expression of tumor necrosis factor-␣ and inducible nitric oxide (NO) synthase (iNOS), and endothelial dysfunction. [1][2][3][4][5][6] Hyperhomocysteinemia-induced oxidative stress may occur as a result of decreased expression and/or activity of key antioxidant enzymes as well as increased enzymatic generation of superoxide anion (the precursor for multiple reactive oxygen and reactive nitrogen species). 2,4 Do hyperhomocysteinemia-induced changes occur in the cerebral circulation and why are they potentially important? Hyperhomocysteinemia is a an emerging risk factor for carotid artery disease (atherosclerosis) and stroke and is associated with Alzheimer's disease and vascular dementia. 7-11 It was not until relatively recently, however, that experimental studies began to define the impact of hyperhomocysteinemia on cerebral vascular biology and the molecular mechanisms that account for these changes. This work has been facilitated by the development of mouse models with genetic alterations in different components of the homocysteine metabolic pathway (see below).Early work in the cerebral microcirculation observed that acute local administration of a very high concentration of homocysteine (1 mmol/L) in the presence of exogenous Cu 2ϩ produced superoxide-mediated reductions in resting cerebral blood flow (CBF) as well as attenuation of endotheliumdependent and NO-mediated responses. 12 Our group was among the first to show that mild chronic hyperhomocysteinemia produces endothelial dysfunction in the carotid artery. 1,13 Moderate hyperhomocysteinemia, induced by acute methionine loading, produces impaired autoregulatory responses in older humans. 14 When considering the consequences of impairment of normal endothelial function, it is important to recall that genetic analyses have demonstrated cosegregation of endothelial dysfunction with a stroke-prone phenotype, 15 and endothelial dysfunction is emerging as an independent predictor of clinical events including stroke. 16 Levels of circulating homocysteine are determined by multiple mechanisms including genetic and dietary factors. Several genetically altered mice deficient in key enzymes within the homocysteine metabolic pathway have now been developed. 17 These include mice deficient in expression of cystathionine ␤-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), and methione synthase (MS). 17 All these genetic alterations result in hyperhomocysteinemia, the magnitude of which is dependent on the content of methionine, folate, and choline in the diet. The development of these animals, along with combined dietary interventions, now allows mechanistic studies of effects of mild to moderate hyperhomocysteinemia on the vasculature. We have used these novel genetic models in studies of ...

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“…Da un lato, il training aumenta l'espressione di ossido nitrico sintetasi endoteliale (e-NOS), con conseguente aumento dell'attività biologica dell'ossido nitrico [70]. Tale aumento si traduce in un'accentuazione della risposta dilatatoria arteriosa all'infusione di acetilcolina, e in un aumento della risposta vasomotoria endotelio-dipendente dell'arteria brachiale [71][72][73][74]. Dall'altro, il training fisico aumenta l'attività dell'enzima superossido dismutasi, in particolar modo della subunità extracellulare (ec-SOD), che si traduce in una ridotta reazione di inattivazione dell'ossido nitrico da parte degli anioni superossido [75].…”

Section: Aspetti Fisiopatologiciunclassified

“…E stato così evidenziato non solo il suo coinvolgimento nelle reazioni di sintesi degli acidi nucleici (DNA e RNA) e la sua stretta correlazione con la vitamina B12, ma anche nelle malattie vascolari tromboemboliche, nelle malattie cardiovascolari, associato secondo alcuni alla vitamina B12 [69,70], nella depressione [30], molto verosimilmente nella demenza senile e nell'Alzheimer [31,[72][73][74], in alcune forme neoplastiche dell'intestino [75]. Il suo deficit nell'insorgenza delle anomalie del tubo neurale, oramai noto da tempo, ha suggerito la fortificazione delle farine di più comune impiego per aumentare, in tutta la popolazione comprese le donne con possibile gravidanza non programmata (50%), i bassi livelli nell'organismo di tale vitamina secondari soprattutto allo scarso consumo di legumi, vegetali e frutta.…”

Section: Conclusioniunclassified

Hyperhomocysteinemia in developing age and nutritional aspects of folates: an early cardiovascular risk factor

Caramia¹,

Belardinelli²

2016

Monaldi Arch Chest Dis

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RASSEGNA IntroduzioneAlcune malattie dell'età evolutiva sono causate da mutazioni di geni che codificano proteine specifiche con conseguente alterazione della struttura e/o della quantità di proteina sintetizzata. Ne derivano degli errori congeniti del metabolismo in quanto, la capacità funzionale della proteina, sia essa un elemento strutturale o un enzima, o un recettore, o un veicolo di trasporto, o una pompa di membrana, può essere più o meno compromessa.Molte mutazioni genetiche sono prive di conseguenze e determinano solo quel polimorfismo che differenzia gli individui. Altre volte gli errori congeniti del metabolismo che ne derivano danno luogo ad una sintomatologia o ad uno stato di malattia variabile, da molto lieve a letale, nella prima infanzia o nell'età evolutiva o più tardi ancora nel giovane adulto e nell'anziano.Una tale situazione si può verificare anche nel ciclo metabolico dell'aminoacido essenziale metionina. Questa, introdotta con alcuni alimenti quali carne, latte, uova, ma anche fagioli e legumi, per la perdita di un gruppo metilico dà luogo alla formazione di circa 26 mmoli di omocisteina attraverso l'attivazione della metionina ad adenosilmetionina (SAMe), donatore universale del gruppo metilico, che ceduto il metile produce adenosilomocisteina la quale per idrolisi libera omocisteina e adenosina.L'omocisteina può essere a sua volta trasformata di nuovo in metionina attraverso un processo di rimetilazione. Questa reazione risparmiatrice di metionina è catalizzata dall'enzima metionina sintetasi (MS) che richiede il 5 metil-tetraidrofolato (MTHF) come substrato e la metilcobalamina come cofattore per trasferire il gruppo metilico del MTHF all'omocisteina: si formano così metionina e tetraidrofolato (THF). Il ciclo tende a conservare metionina che, nella forma attivata (SAMe), è il maggior donatore di metili per DNA, RNA, etc. [1,2].A livello epatico, dove il metabolismo della metionina è particolarmente attivo, oltre all'enzima folato-dipendente è presente un altro enzima che produce per metilazione metionina da omocisteina: è una metiltransferasi che utilizza come donatore di metili la betaina o trimetilglicina.Se la metionina è introdotta in eccesso viene inibita la metionina sintetasi, per ridurre la sintesi di metionina, e si attiva, con una serie di reazioni di transulfurazione irreversibile ad opera di due enzimi vitamina B6 dipendenti, la Cistationina-β-sintasi e la β-Cistationasi, per formare cistationina e cisteina During the last decade, scientific evidence is mounting that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Despite this evidence, however, there are still concerns about the mechanisms(s) by which homocysteine exerts its pro-atherogenic effect, and it is unclear whether the decreased plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk. Experimental studies have shown that many possible mechanisms are implicated in the pro-atherog...

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Homocysteine and Alzheimer's disease

Cited by 336 publications

References 29 publications

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Methionine gamma‐lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers

Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction

Hyperhomocysteinemia in developing age and nutritional aspects of folates: an early cardiovascular risk factor

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