Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir

In human, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design. This work reports the first crystallographic Study of human PNP complexed with acyclovir (HsPNP:Acy). Acyclovir is a potent clinically useful inhibitor of replicant herpes simplex virus that also inhibits human PNP but with a relatively lower inhibitory activity (K-i=90muM). Analysis of the structural differences among the HsPNP:Acy complex, PNP apoenzyme, and HsPNP:Immucillin-H provides explanation for inhibitor binding, refines the purine-binding site, and can be used for future inhibitor design. (C) 2003 Published by Elsevier B.V.

Unilateral Facial Paralysis Caused by Ramsay Hunt Syndrome

The Ramsay Hunt syndrome is a rare disease caused by an infection of the geniculate ganglion by the varicella-zoster virus. The main clinical features of the syndrome are as follows: Bell palsy unilateral or bilateral, vesicular eruptions on the ears, ear pain, dizziness, preauricular swelling, tingling, tearing, loss of taste sensation, and nystagmus. We describe a 23-year-old white woman, who presented with facial paralysis on the left side of the face, pain, fever, ear pain, and swelling in the neck and auricular region on the left side. She received appropriate treatment with acyclovir, vitamin B complex, and CMP nucleus. After 30 days after presentation, the patient did not show any signs or symptoms of the syndrome. At follow-up at 1 year, she showed no relapse of the syndrome.

New catalytic mechanism for human purine nucleoside phosphorylase

Human purine nucleoside phosphorylase has been submitted to intensive structure-based design of inhibitors, most of them using low-resolution structures of human PNP. Recently, several structures of human PNP have been reported, which allowed redefinition of the active site and understanding of the structural basis for inhibition of PNP by acyclovir and immucillin-H. Based on previously solved human PNP structures, we proposed here a new catalytic mechanism for human PNP, which is supported by crystallographic studies and explains previously determined kinetic data. (C) 2004 Elsevier B.V. All rights reserved.