Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine

Bongiovanni, Rodolfo; Young, Damon; Newbould, Erica; Jaskiw, George E.

doi:10.1016/j.brainres.2006.07.074

Cited by 16 publications

(15 citation statements)

References 72 publications

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“…The measured decrease in brain Tyr levels did not result in a corresponding change in either NE or DA, likely because tyrosine hydroxylase, the rate-limiting enzyme in the generation of NE and DA, is close to full saturation with the tyrosine substrate, so changes in availability do not alter the net biosynthetic capability (31). Indeed, prior studies show only a limited sensitivity of NE and DA to circulating Tyr levels (8,20). In contrast, tryptophan hydroxylase, the ratelimiting enzyme in the synthetic pathway of 5-HT, is subsaturated at normal levels of Trp, the AAA precursor for this transmitter (9,77).…”

Section: Discussionmentioning

confidence: 74%

Branched-chain amino acids alter neurobehavioral function in rats

Coppola

Wenner²,

Ilkayeva³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Newgard CB. Branched-chain amino acids alter neurobehavioral function in rats. Am J Physiol Endocrinol Metab 304: E405-E413, 2013. First published December 18, 2012 doi:10.1152/ajpendo.00373.2012.-Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high-sucrose or a high-fat diet with BCAA induces anxiety-like behavior in rats compared with control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high-energy diets with BCAA causes neurobehavioral impairment. Since BCAA are elevated spontaneously in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.branched-chain amino acids; tryptophan; mood disorders; obesity IN THE PAST FEW DECADES, changes in food consumption and sedentary living conditions have contributed to a worldwide obesity epidemic, including in the US, where more than 34% of adults are obese (44,45). Given the high prevalence of obesity and mood disorders, there is an increasing interest in the relationship of these two conditions (2,17,25,33,42,58,62) and in the concept that overnutrition may have a direct causal link to impairment of mental function.Recent studies have revealed that a cluster of metabolites comprised of the branched-chain amino acids (BCAA) leucine (Leu), isoleucine (Ile), and valine (Val) and their metabolites, as well as the aromatic amino acids (AAA) tyrosine (Tyr) and phenylalanine (Phe), are strongly associated with obesity and insulin resistance in humans (1,10,29,43,67,78). Moreover, a very similar metabolite cluster predicts incident type 2 diabetes in longitudinal studies in humans (64) and, when measured at baseline in obese subjects, also predicts improvement in insulin sensitivity in response to a dietary/behavioral weight loss intervention (63). These findings suggest the possibility that elevated BCAA could be linked to behavioral disorders.BCAA are transported from the blood into the central nervous system (CNS) through the blood-brain barrier (BBB) by the large neutral amino acid transporter 1 (LAT1) (47). LAT1 transports ...

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Section: Discussionmentioning

confidence: 74%

Branched-chain amino acids alter neurobehavioral function in rats

Coppola

Wenner²,

Ilkayeva³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…normal concentration of cellular tyrosine in the brain [9] is in the range 100-125 mM; the midpoint of this range is close to the maximum of the velocity curve. However, this ''normal concentration'' is, in fact, a daily average because the tyrosine concentration in the brain varies by as much as a factor of two before and after meals [10].…”

Section: Tyrosine Hydroxylasementioning

confidence: 70%

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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“…In order for TYR administration to augment DA synthesis and/or efflux, the availability of TYR rather than activity of tyrosine hydroxylase must become rate limiting for DA synthesis; this normally requires activation of tyrosine hydroxylase as well and/or a lowering of tyrosine availability (Bongiovanni et al, 2005; Jaskiw and Bongiovanni, 2004; Jaskiw et al, 2001, 2005, 2008; Milner and Wurtman, 1986). HAL, for instance, potently activates tyrosine hydroxylase (Salvatore et al, 2000; Zivkovic and Guidotti, 1974) and modestly lowers TYR levels in striatal tissue (Bongiovanni et al, 2006; Westerink and Wirix, 1983). We had previously posited that superimposing a primary NAA(−)-mediated TYR depletion on a HAL-activated nigrostriatal DA system makes TYR availability rate-limiting for DA synthesis and hence explains why administered TYR attenuates the ability of NAA(−) to potentiate HAL-induced catalepsy (Jaskiw and Bongiovanni, 2004).…”

Section: Discussionmentioning

confidence: 99%

Acute lithium administration selectively lowers tyrosine levels in serum and brain

McFarlane¹,

Steele²,

Vinion³

et al. 2011

Brain Research

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Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl2) 3.0 mEq/kg IP acutely lowered serum TYR and the ratio of serum TYR to other large neutral amino acids (LNAAs); it also selectively lowered striatum TYR levels as measured in tissue or in vivo. While LiCl2 3.0 mEq/kg IP also augmented haloperidol (0.19 mg/kg SC)-induced catalepsy, this lithium effect was not attenuated by administration of TYR 100 mg/kg IP. We conclude that lithium acutely and selectively lowers brain TYR by lowering serum levels of tyrosine relative to the LNAAs that compete with it for transport across the blood–brain barrier. However, the lowering of TYR does not appear to significantly contribute to the ability of lithium to potentiate haloperidol-mediated catalepsy.

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Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine

Cited by 16 publications

References 72 publications

Branched-chain amino acids alter neurobehavioral function in rats

Branched-chain amino acids alter neurobehavioral function in rats

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

Acute lithium administration selectively lowers tyrosine levels in serum and brain

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