d(GC) - Association of Biotechnology and Pharmacy
d(GC) - Association of Biotechnology and Pharmacy
d(GC) - Association of Biotechnology and Pharmacy
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Current Trends in <strong>Biotechnology</strong> <strong>and</strong> <strong>Pharmacy</strong><br />
Vol. 6 (2) 204-209 April 2012, ISSN 0973-8916 (Print), 2230-7303 (Online)<br />
First Evidence for Aluminum-maltol driven B to Z-DNA<br />
Conformational Transition in Poly d(<strong>GC</strong>). d(<strong>GC</strong>):<br />
Relevance to Alzheimer’s Disease<br />
M. Govindaraju1,4 , Monica F.S. 2, 3 , Berrocal R3 ., Sambasiva Rao K.R.S. 4 <strong>and</strong> Rao K.S. 3*<br />
1Molecular Biophysics Unit, Indian Institute <strong>of</strong> Science, Bangalore, India<br />
2Columbus University College <strong>of</strong> Medicine <strong>and</strong> Health Sciences, Republic Panama<br />
3INDICASAT-AIP, City <strong>of</strong> Knowledge, Republic Panama<br />
4Department <strong>of</strong> <strong>Biotechnology</strong>, Acharya Nagarjuna University, Guntur, India<br />
*For Correspondence - kjr5n2009@gmail.com<br />
Abstract<br />
Higher concentration <strong>of</strong> Aluminum (Al)<br />
has been observed in Alzheimer’s, Parkinson’s,<br />
<strong>and</strong> Amyotrophic lateral sclerosis <strong>and</strong> there was<br />
an apparent localization <strong>of</strong> the Al in chromatin in<br />
the brain cells. Studies <strong>of</strong> Al-DNA interaction<br />
showed that cross-linking occurs in DNAs <strong>of</strong> all<br />
base ratios, including poly d(AT).d(AT) <strong>and</strong> poly<br />
d(<strong>GC</strong>).d(<strong>GC</strong>). In the present investigation,<br />
interaction <strong>of</strong> Al with poly d(<strong>GC</strong>).d(<strong>GC</strong>) <strong>and</strong> poly<br />
d(AT).d(AT) was studied using Al-maltol, a<br />
hydrolytically stable Al-compound, at neutral pH.<br />
We found that Al at micromolar level caused<br />
conformational transition from B-DNA to Z-DNA<br />
in poly d(<strong>GC</strong>). d(<strong>GC</strong>). Chelation by EDTA could<br />
reverse the Z-DNA caused by Al-maltol back to<br />
+ B- DNA. We propose that Al(mal) <strong>and</strong> Al(mal)<br />
2<br />
2+ , major cationic species <strong>of</strong> Al-maltol at neutral<br />
pH are involved in the above transition in poly<br />
d(<strong>GC</strong>).d(<strong>GC</strong>). The biological relevance <strong>of</strong> DNA<br />
transition in Alzheimer’s disease is discussed.<br />
Key words : Aluminum maltol, DNA transition,<br />
EDTA, Z DNA<br />
Introduction<br />
The interest in the biological role <strong>of</strong><br />
Aluminum has been stimulated by its debatable<br />
involvement in Alzheimer’s disease (1-3), dialysis<br />
encephalopathy (4) <strong>and</strong> ALS- Parkinson<br />
dementia in Gaum <strong>and</strong> Kii peninsula (5-6),<br />
204<br />
Aluminum has been found in the nuclear region<br />
<strong>of</strong> brain neuronal cells that contain neur<strong>of</strong>ibriallry<br />
tangles, in Alzheimer’s disease <strong>and</strong> ALS-<br />
Parkinson dementia (7-8). Aluminum is reported<br />
to be associated with cellular toxicity through its<br />
interaction with DNA (9). More detailed studies<br />
located the aluminum in the chromatin <strong>of</strong> brain<br />
neuronal nuclei both in Alzheimer’s victims <strong>and</strong><br />
in animals subjected to CNS injection <strong>of</strong><br />
aluminum (9-12). Alzheimer’s disease is complex<br />
neurodegenerative disorder in which etiological<br />
factors are not clearly established although<br />
unproven hypothesis have included trauma,<br />
aluminum toxicity <strong>and</strong> infectious agents (13 -15).<br />
We reported that the genomic DNA in the<br />
hippocampus <strong>of</strong> the Alzheimer’s brain undergoes<br />
helical transition from B-DNA to Z-DNA. We<br />
hypothesized that aluminum, abnormal proteins<br />
like Ab <strong>and</strong> tau, oxidative stress, <strong>and</strong> metal<br />
homeostasis might play role in the conformational<br />
transition (16). In the present investigation<br />
Aluminum maltol, an Al compound was tested<br />
for its interaction with Poly d(<strong>GC</strong>).d(<strong>GC</strong>) <strong>and</strong> Poly<br />
d(AT).d(AT). Karlik <strong>and</strong> Eichhorn (17) reported that<br />
interaction <strong>of</strong> Al with Poly d(<strong>GC</strong>). d(<strong>GC</strong>) using<br />
aluminum chloride results in cross linking <strong>of</strong> DNA<br />
by aluminum without any conformational change.<br />
Previous studies from our lab reported that Al-maltol<br />
could induce Z-DNA in (CCG) 12 repeats at neutral<br />
pH (18). Since the effects <strong>of</strong> aluminum depend<br />
First evidence for Aluminum-maltol driven B to Z-DNA