The strong inhibition of triosephosphate isomerase by the natural β-carbolines may explain their neurotoxic actions

Bonnet, R.; Pavlović, Sanja; Lehmann, Jochen; Rommelspacher, Hans

doi:10.1016/j.neuroscience.2004.05.002

Cited by 33 publications

(23 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, it was proposed that even in the absence of exogenous toxins, endogenous toxins derived from metabolism could have similar consequences. One example is the natural ␤-carbolines (BC), endogenous neurotoxins formed from tryptophan and related compounds, which closely resemble MPTP in structure (39). Injection of BC into the substantia nigra in animal models cause neurodegeneration.…”

Section: Methyglyoxal and Ages May Be Linked With Other Neurologicalmentioning

confidence: 99%

“…However, the mechanism of BC (and MPTP) toxicity remains unknown. Recent studies demonstrate that BC binds with very high affinity to Tpi and is an extremely potent inhibitor of its enzymatic activity (39). Thus, decreased Tpi activity, and a resultant increase in AGEs, could be an important factor contributing to Parkinson's disease.…”

Section: Methyglyoxal and Ages May Be Linked With Other Neurologicalmentioning

confidence: 99%

See 1 more Smart Citation

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

Gnerer

Kreber

Ganetzky

2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

To identify genes required for maintaining neuronal viability, we screened our collection of Drosophila temperature-sensitive paralytic mutants for those exhibiting shortened lifespan and neurodegeneration. Here, we describe the characterization of wasted away (wstd), a recessive, hypomorphic mutation that causes progressive motor impairment, vacuolar neuropathology, and severely reduced lifespan. We demonstrate that the affected gene encodes the glycolytic enzyme, triosephosphate isomerase (Tpi). Mutations causing Tpi deficiency in humans are also characterized by progressive neurological dysfunction, neurodegeneration, and early death. In Tpi-deficient flies and humans, a decrease in ATP levels did not appear to cause the observed phenotypes because ATP levels remained normal. We also found no genetic evidence that the mutant Drosophila Tpi was misfolded or involved in aberrant protein-protein associations. Instead, we favor the hypothesis that mutations in Tpi lead to an accumulation of methylglyoxal and the consequent enhanced production of advanced glycation end products, which are ultimately responsible for the death and dysfunction of Tpi-deficient neurons. Our results highlight an essential protective role of Tpi and support the idea that advanced glycation end products may also contribute to pathogenesis of other neurological disorders.advanced glycation end product

show abstract

Section: Methyglyoxal and Ages May Be Linked With Other Neurologicalmentioning

confidence: 99%

Section: Methyglyoxal and Ages May Be Linked With Other Neurologicalmentioning

confidence: 99%

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

Gnerer

Kreber

Ganetzky

2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In addition to reduced energy production, these diseases often have additional phenotypes. For example, triosephosphate isomerase deficiency results in a build-up of dihydroxyacetone phosphate which is believed to be toxic, a result which is recapitulated by inhibitors of the enzyme [27,32]. Therefore, it is expected that inhibition of key metabolic enzymes in helminth pathogens would lead to numerous deleterious pharmacological effects which would kill (or severely harm) the organism.…”

Section: The Potentials and Pitfalls Of Targeting Metabolic Enzymesmentioning

confidence: 99%

Metabolic enzymes of helminth parasites: potential as drug targets

Timson¹

2015

CPPS

View full text Add to dashboard Cite

Metabolic pathways which extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials which target phosphofructokinase and Clorsulon which targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics which target metabolic enzymes.

show abstract

“…Abs binding to TPI and GAPDH in neurons and axons may block membrane translocation and may also inhibit enzymes that serve to preserve neuronal integrity and neuronal glycolytic activity (37). Recent studies have shown that binding of inhibitors like the natural ␤-carbolines or ␣-monochlorohydrin to TPI and GAPDH causes decreased neuronal ATP production followed by progressive neuronal degeneration and death (38,39). Inhibition of TPI activity by Abs has been reported in hepatitis A virus infections (40).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Recently, it has been shown that NO elicits S-nitrosylation of GAPDH and subsequently translocation of GAPDH protein into the nucleus, which results in DNA fragmentation and apoptosis of cerebral granular cells (41). NO-S-nitrosylation-GAPDH cascade has been shown to play an important role in cytotoxicity in neuronal death (38). NO is synthesized by activation of different isoforms of NO synthases, including inducible NO synthase, that have been found to be a marker of brain inflammation in MS (42)(43)(44).…”

Section: Downloaded Frommentioning

confidence: 99%

Triosephosphate Isomerase- and Glyceraldehyde-3-Phosphate Dehydrogenase-Reactive Autoantibodies in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Kölln¹,

Ren²,

Da³

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B cells in the cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) bind to axons in MS brains. To study the axonal Ags involved in MS, we identified the glycolytic enzymes, triosephosphate isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B cells in the CSF and in lesions from MS patients. Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), clinically isolated syndrome (CIS) suggestive of MS (40%), other inflammatory neurological diseases (OIND; 29%), and other noninflammatory neurological diseases (ONIND; 31%). Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%). The coexistence of both autoantibodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND. Two scFv-Abs generated from the CSF and from lesions of a MS brain showed immunoreactivity to TPI and GAPDH, respectively. The findings suggest that TPI and GAPDH may be candidate Ags for an autoimmune response to neurons and axons in MS.

show abstract

The strong inhibition of triosephosphate isomerase by the natural β-carbolines may explain their neurotoxic actions

Cited by 33 publications

References 34 publications

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

Metabolic enzymes of helminth parasites: potential as drug targets

Triosephosphate Isomerase- and Glyceraldehyde-3-Phosphate Dehydrogenase-Reactive Autoantibodies in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Contact Info

Product

Resources

About