Therapeutic implication of L-phenylalanine aggregation mechanism and its modulation by D-phenylalanine in phenylketonuria.
Self-assembly of phenylalanine is linked to amyloid formation toxicity in phenylketonuria disease. We are demonstrating that L-phenylalanine self-assembles to amyloid fibrils at varying experimental conditions and transforms to a gel state at saturated concentration. Biophysical methods including nuclear magnetic resonance, resistance by alpha-phenylglycine to fibril formation and preference of protected phenylalanine to self-assemble show that this behaviour of L-phenylalanine is governed mainly by hydrophobic interactions. Interestingly, D-phenylalanine arrests the fibre formation by L-phenylalanine and gives rise to flakes. These flakes do not propagate further and prevent fibre formation by L-phenylalanine. This suggests the use of D-phenylalanine as modulator of L-phenylalanine amyloid formation and may qualify as a therapeutic molecule in phenylketonuria.
Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, Uttar Pradesh, India.
Virender
V
Singh
Centre of Biomedical Research, SGPGIMS Campus, Raibarelly Road, Lucknow 226014, Uttar Pradesh, India.
Ratan Kumar
RK
Rai
CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
Ashish
A
Arora
Centre of Biomedical Research, SGPGIMS Campus, Raibarelly Road, Lucknow 226014, Uttar Pradesh, India.
Neeraj
N
Sinha
Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, Uttar Pradesh, India.
Ashwani Kumar
AK
Thakur
D006801:Humans; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D019906:Nuclear Magnetic Resonance, Biomolecular; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D010661:Phenylketonurias / Q000188:drug therapy*; D013237:Stereoisomerism
D010649:Phenylalanine