Fatty Acid Modulated Human Serum Albumin Binding of the β-Carboline Alkaloids Norharmane and Harmane

Domonkos, Celesztina; Fitos, Ilona; Visy, Júlia; Zsila, Ferenc

doi:10.1021/mp400531n

Cited by 21 publications

(14 citation statements)

References 37 publications

(115 reference statements)

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“…It forms a π-π stacking interaction with Y411 at 3.52 Å ( Fig 5C ). This binding is similar to the binding behaviour of nonharmane [ 35 ] and Bcl2 family anticancer agent [ 36 ] as previously reported. In addition to this, the FA4 backbone stabilization role of π-alkyl interactions with Subdomain IIIA residues V426 at 4.91Å and L460 at 5.17 Å is observed.…”

Section: Discussionsupporting

confidence: 88%

Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to Human Serum Albumin at Fatty Acid Binding Sites

et al. 2015

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Endoplasmic reticulum stress elicits unfolded protein response to counteract the accumulating unfolded protein load inside a cell. The chemical chaperone, 4-Phenylbutyric acid (4-PBA) is a FDA approved drug that alleviates endoplasmic reticulum stress by assisting protein folding. It is found efficacious to augment pathological conditions like type 2 diabetes, obesity and neurodegeneration. This study explores the binding nature of 4-PBA with human serum albumin (HSA) through spectroscopic and molecular dynamics approaches, and the results show that 4-PBA has high binding specificity to Sudlow Site II (Fatty acid binding site 3, subdomain IIIA). Ligand displacement studies, RMSD stabilization profiles and MM-PBSA binding free energy calculation confirm the same. The binding constant as calculated from fluorescence spectroscopic studies was found to be kPBA = 2.69 x 105 M-1. Like long chain fatty acids, 4-PBA induces conformational changes on HSA as shown by circular dichroism, and it elicits stable binding at Sudlow Site II (fatty acid binding site 3) by forming strong hydrogen bonding and a salt bridge between domain II and III of HSA. This minimizes the fluctuation of HSA backbone as shown by limited conformational space occupancy in the principal component analysis. The overall hydrophobicity of W214 pocket (located at subdomain IIA), increases upon occupancy of 4-PBA at any FA site. Descriptors of this pocket formed by residues from other subdomains largely play a role in compensating the dynamic movement of W214.

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Section: Discussionsupporting

confidence: 88%

Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to Human Serum Albumin at Fatty Acid Binding Sites

et al. 2015

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“…Free BC can enter the brain, whereas the albumin bound fraction cannot. Albumin binding of BC requires, however, a unique co-binding of free fatty acids 10 . French fries have been found to correlate inversely with ALS risk 7 , whereas a very low body mass index, in particular in adolescence and young adulthood is carrying a risk to develop the disease later in life 1,2 .…”

Section: Environmental Risks For Smnd/als In Particular Hypothetical mentioning

confidence: 99%

The Why of Sporadic Motor Neuron Disease - Many Factors, still a Mystery?

Krone¹

2016

J Neurol Neuromedicine

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The sporadic forms of motor neuron diseases seem to depend on a multitude of factors that are, however, largely speculative. A main endogenous factor is seen in the enhanced expression of human endogenous retroviruses (HERVs). It is supposed that this is affecting the biogenesis of neuromelanin, in particular in the locus coeruleus. An altered neuromelanin with increased storage of metals and of precursors for toxins from food, respectively, might be of central importance. A hypothesis is described that is able to explain a number of observations and to understand roles and interactions of different factors. Toxins affecting the excitatory system are formed apparently within altered neuromelanin. Moreover, neuromelanin loaded with metal is also a microenvironment where pathological variants of proteins such as of alphasynuclein are generated. Familial and toxin related forms of the diseases merge in formation and deposition of aberrant proteins and in a failure to destroy superoxide, thus increasing the harm from oxidative and nitrosative stress. This view might give some rational to revive investigations in methods for stabilization of storage and cautious squeezing out of metals and toxicants from neuromelanin, relying eventually on melatonin, iron chelators and chloroquine, respectively.

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“…Interaction of various NMs with the most abundant human serum albumin (HSA) has been investigated [ 74 , 75 ]. Systematic studies on the interaction of the main drug binding components of human plasma HSA or alpha 1 -acid glycoprotein (AGP) with NMs may possibly influence not only the free concentrations of exogenous and endogenous ligands [ 76 , 77 ], however, the biodistribution of NMs as well.…”

Section: Unique Biodistribution Of Nms and Pertaining Model Systemmentioning

confidence: 99%

The Janus Facet of Nanomaterials

Kardos

Jemnitz

Jablonkai

et al. 2015

BioMed Research International

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Application of nanoscale materials (NMs) displays a rapidly increasing trend in electronics, optics, chemical catalysis, biotechnology, and medicine due to versatile nature of NMs and easily adjustable physical, physicochemical, and chemical properties. However, the increasing abundance of NMs also poses significant new and emerging health and environmental risks. Despite growing efforts, understanding toxicity of NMs does not seem to cope with the demand, because NMs usually act entirely different from those of conventional small molecule drugs. Currently, large-scale application of available safety assessment protocols, as well as their furthering through case-by-case practice, is advisable. We define a standard work-scheme for nanotoxicity evaluation of NMs, comprising thorough characterization of structural, physical, physicochemical, and chemical traits, followed by measuring biodistribution in live tissue and blood combined with investigation of organ-specific effects especially regarding the function of the brain and the liver. We propose a range of biochemical, cellular, and immunological processes to be explored in order to provide information on the early effects of NMs on some basic physiological functions and chemical defense mechanisms. Together, these contributions give an overview with important implications for the understanding of many aspects of nanotoxicity.

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Fatty Acid Modulated Human Serum Albumin Binding of the β-Carboline Alkaloids Norharmane and Harmane

Cited by 21 publications

References 37 publications

Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to Human Serum Albumin at Fatty Acid Binding Sites

Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to Human Serum Albumin at Fatty Acid Binding Sites

The Why of Sporadic Motor Neuron Disease - Many Factors, still a Mystery?

The Janus Facet of Nanomaterials

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