Aspartic Proteinases: Retroviral and Cellular Enzymes

483 Pages·1998·18.637 MB·English

by  Tom L. Blundell, Kunchur Guruprasad, Armando Albert, Mark Williams (auth.), Michael N. G. James (eds.)

ASPARTIC PROTEINASES
Retroviral and Cellular Enzymes
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
Recent Volumes in this Series
Volume 427
DIETARY FIBER IN HEALTH AND DISEASE
Edited by David Kritchevsky and Charles Bonfield
Volume 428
OXYGEN TRANSPORT TO TISSUE XIX
Edited by David K. Harrison and David T. Delpy
Volume 429
BRAIN PLASTICITY: Development and Aging
Edited by Guido Filogamo, Antonia Vernadakis, Fulvia Gremo, Alain M. Privat,
and Paola S. Timiras
Volume 430
ANALYTICAL AND QUANTITATIVE CARDIOLOGY
Edited by Samuel Sideman and Rafael Beyar
Volume 431
PURINE AND PYRIMIDINE METABOLISM IN MAN IX
Edited by Andrea Griesmacher, Peter Chiba, and Mathias M. Miiller
Volume 432
HYPERTENSION AND THE HEART
Edited by Alberto Zanchetti, Richard B. Devereux, Lennart Hansson, and Sergio Gorini
Volume 433
RECENT ADVANCES IN PROSTAGLANDIN, THROMBOXANE, AND
LEUKOTRIENE RESEARCH
Edited by Helmut Sinzinger, Bengt Samuelsson, John R. Vane, Rodolfo Paoletti,
Peter Ramwell, and Patrick Y-K Wong
Volume 434
PROCESS-INDUCED CHEMICAL CHANGES IN FOOD
Edited by Fereidoon Shahidi, Chi-Tang Ho, and Chuyen Van Nguyen
Volume 435
GL YCOIMMUNOLOGY 2
Edited by John S. Axford
Volume 436
ASPARTIC PROTEINASES: Retroviral and Cellular Enzymes
Edited by Michael N. G. James
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume
immediately upon publication. Volumes are billed only upon actual shipment. For funher information please contact
the publisher.
ASPARTIC PROTEINASES
Retroviral and Cellular Enzymes
Edited by
Michael N. G. James
University of Alberta
Edmnonton,Alberta,C8nada
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging in Publication Data
Aspartic proteinases: retroviral and cellular enzymes I edited by Michael N. G. James.
p. cm.-(Advances in experimental medicine and biology; v. 436)
"Proceedings of the Seventh International Conference on Aspartic Proteinases, held Octo-
ber 22-27, 1996, in Banff, A1berta, Canada"-T.p. verso.
Includes bibliographical references and index.
ISBN 978-1-4613-7452-7 ISBN 978-1-4615-5373-1 (eBook)
DOI 10.1007/978-1-4615-5373-1
1. Aspartic proteinases-Congresses. 1. James, Michael N. G. II. International Conference
on Aspartic Proteinases (7th: 1996: Banff, Alta.) III. Series.
[DNLM: 1. Aspartic Proteinases-metabolism-congresses. 2. Aspartic Proteinases
chemistry-congresses. 3. Retroviridae-enzymology-congresses. 4. Protease Inhibitors
congresses. Wl AD559 v. 436 1998 I QU 136 S926 1998]
QP609.A86S77 1998
572'.76-dc21
DNLM/DLC 97-52057
for Library of Congress CIP
Proceedings of the Seventh International Conference on Aspartic Proteinases,
held October 22-27, 1996, in Banff, Alberta, Canada
ISBN 978-1-4613-7452-7
© 1998 Springer Science+Business Media New York
Origina1ly published by Plenum Plenum Press in 1998
Softcover reprint of the hardcover 1s t edition 1998
AII rights reserved
No part ofthis book may be reproduced, stored in a retrieval system, or transmitted in any form or by any
means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without writ!en
permission from the Publisher
PREFACE
The VIIth International Conference on Aspartic Proteinases was held in Banff,
Alberta, Canada, from October 22 to 27, 1996. The venue was the Banff Centre in the
Canadian Rockies, a setting well known worldwide for the scenic beauty and mountain
grandeur. It was perhaps presumptuous of the organizers to call this the seventh Aspartic
Proteinase Conference but it was felt that the meeting in 1982, organized by Tom Blundell
and John Kay, was of an international stature and covered topics sufficiently broad to
constitute a conference. Thus, there is a discontinuity in that the Gifu Conference organized
by Prof. Kenji Takahashi was the fifth International Conference on Aspartic Proteinases.
Officially, there has not been a sixth Conference and if there is confusion, it is the result of
my desire to recognize the importance of the London meeting.
Banffhosted 106 scientists from 14 different countries. There were 26 invited speak
ers among the 44 oral presentations of the 7 main sessions. In addition, there were 53 con
tributed poster presentations that spanned the whole range of interest in aspartic proteinases.
In planning this conference, we departed slightly from the traditional order of the
topics. The retroviral aspartic proteinases constituted the first day of presentations and it
was necessary to have two sessions to cover all of the areas of interest. Cathepsin D and
cathepsin E dominated the presentations in the Mammalian Aspartic Proteinases session,
an area that has traditionally been dominated by papers on the stomach enzymes: pepsin,
chymosin and gastricsin. Session 4 was on aspartic proteinase zymogens and the process
of conversion of these molecules to active enzymes. Although this session was relatively
small, the ensuing discussion was heated and lively. The aspartic proteinases from Can
dida, Aspergillus niger and Rhizomucor miehei replaced the fungal enzymes, endothiapep
sin, rhizopuspepsin and penicillopepsin in the Microbial Aspartic Proteinases session. The
aspartic proteinases and inhibitors from parasites were discussed in a new session at this
meeting. The most widely discussed member of this branch of the aspartic proteinase fam
ily was malarial plasmepsin from Plasmodium Jalciparum. The seventh and final session
was devoted to plant aspartic proteinases, in particular cardosin from Cynara cardunculus.
John Kay and Ben Dunn were extremely helpful in the planning stages of this
conference. Their wise counsel in selecting speakers was most appreciated. The members
of my laboratory devoted a great deal of time and effort to the successful organization and
running of the conference. Masao Fujinaga was ever vigilant in scanning bibliographic
databases for new papers on aspartic proteinases. In addition to their scientific contribu
tions, Marie Fraser, Katherine Bateman, Nina Khazanovich and Amir Khan made sure that
the conference paraphernalia, tote bags, T-shirts, coffee mugs, pens, paper etc. were avail
able and ready at the time of the conference.
v
vi Preface
I want to express a very special note of thanks to Mae Wylie for her dedication and
untiring hard work in making this conference a success. She did so many things that made
the conference a pleasure for all of the attendees. I am sure that everyone joins me in
thanking Mae for her devotion to the meeting.
The VIIth International Conference on Aspartic Proteinases would not have hap
pened without the very generous financial support from the many public and private
organizations listed on the accompanying page of Acknowledgements. The Government of
Alberta through the offices of Alberta Economic Development and Trade and the Alberta
Heritage Foundation for Medical Research was joined in their donations by grants from
the Medical Research Council of Canada, the University of Alberta Conference Fund, and
from the Dean of the Faculty of Medicine. I am very grateful to the corporate sponsors for
their generosity in the light of ever decreasing funding for such meetings.
The concluding session of the conference was a Panel Discussion that looked to the
future and to where the important questions in aspartic proteinase research were directed.
As in the past, there was an interesting mix of structural and functional questions that
were raised. Whereas one of the main themes of previous conferences dealt with mecha
nism, the discussion on this topic seems to have reached a consensus. However, the struc
tural details of the reasons for the different pH optima exhibited by various members of
the family have not been settled.
Members of the panel and conference delegates felt that we are at the brink of
discovery regarding the widespread occurrence of aspartic proteinases in nature. In the
future genomics will certainly bring to light how important these molecules are. Can the
sequence of an aspartic proteinase reveal its membership in the family and its specificity
for substrates? In other words, have our predictive methods been sufficiently refined to
recognize these features for the authentic aspartic proteinases as well as those that might
have adopted other functions (e.g. the pregnancy associated glycoproteins)? A very impor
tant question concerns identifying the naturally occurring substrates for the highly specific
aspartic proteinases. This, as well as defining substrate specificity, will occupy many and
challenge the phage biologists and combinatorial chemists for some time to come. Post
translational modifications clearly playa role in intracellular targetting. Some of these
details have been revealed for cathepsin D and renin. There are many other effects of
insertions or deletions to the canonical sequences that remain to be elucidated. What are
the multitude of other roles for which nature has adapted aspartic proteinases? Can we
deduce these functions from gene knock-outs? The most recent and exciting was the regu
lation of enzymatic activity by dimerization in the retroviral aspartic proteinases.
Clearly, from the wide ranging discussion in that concluding session the aspartic
proteinase field will be active for years to come. I look forward to the next international
conference wherever and whenever it will be held.
Finally, the generosity of the public and private sponsors of our conference allowed
us to present four travel awards to the authors of the four best posters (as judged by an
impartial panel), two for postdoctoral fellows and two for graduate students. The winners
were: Deborah Dauber (San Francisco, USA), Carlos Frazao (Oeiras, Portugal), Karen
Girdwood (Cardiff, Wales) and lIya Kashparov (Moscow, Russia). My sincere congratula
tions to these most deserving young scientists.
The Aspartic Proteinase Conferences now have a 20-year history, since the first one
was organized by Jordan Tang and held in Oklahoma in November 1976. To me the high
light of that meeting was the first public announcements of the tertiary structures of the
three fungal aspartic proteinases endothiapepsin, rhizopus-pepsin and penicillopepsin, as
well as that of porcine pepsin. In the pages of this volume, we are guided through the
Preface vii
fascinating history of the aspartic proteinases in the text of the Plenary Lecture by Tom
Blundell. I thank Tom for his insightful views. The success of this volume is due to all of the
contributors who attended the conference and presented their results and interpretations.
Michael James
Edmonton, Alberta
BOOKS OF RELATED INTEREST
l. Tang, J. (1997) Acid Proteases: Structure, Function, and Biology, Advances in Experimental Medicine and
Biology, vol. 95, New York: Plenum Press.
2. Kostka, V. (1985) Aspartic Proteinases and Their Inhibitors, Proceedings of the FEBS Advanced Course
no. 84/07, Berlin: Walter de Gruyter.
3. Dunn, B. (1991) Structure and Function of the Aspartic Proteinases: Genetics, Structures, and Mecha
nisms, Advances in Experimental Medicine and Biology, vol. 306, New York: Plenum Press.
4. Tahahashi, K. (1993) Aspartic Proteinases: Structure, Function, Biology, and Biomedical Implications,
Advances in Experimental Medicine and Biology, vol. 362, New York: Plenum Press.
ACKNOWLEDGMENTS
The financial support of the following institutions and companies is gratefully
acknowledged:
PUBLIC INSTITUTIONS
Canadian Society for Biochemistry and Molecular Biology
Alberta Heritage Foundation for Medical Research
Alberta Economic Development and Trade
Faculty of Medicine, University of Alberta, Edmonton
University of Alberta Conference Fund, Edmonton
Medical Research Council of Canada
CORPORATE SPONSORS
Abbott Laboratories, Abbott Park, IL, USA
Advanced ChemTech, Inc., Louisville, KY, USA
Agouron Pharmaceuticals, Inc., San Diego, CA, USA
Bayer Corporation, West Haven, CT, USA
Beatrice Foods, Inc., Calgary, Alberta
Beckman Instruments (Canada) Inc., Mississauga, Ontario
Bio-Mega/Boehringer Ingelheim Research Inc., Laval, Quebec
Ciba-Geigy Canada Ltd., Calgary, Alberta
Chiron Corporation, Emeryville, CA, USA
Dupont Merck, Wilmington, DE, USA
Enraf-Nonius Co., New York, NY, USA
Genencor International, South San Francisco, CA, USA
Genentech, Inc., San Francisco, CA, USA
Glaxo Wellcome Inc., Mississauga, Ontario
Glaxo Wellcome Inc., Research Triangle Park, NC, USA
Glaxo Wellcome Research & Development, Stevenage, UK
Hoffmann-La Roche, Basel, Switzerland
Merck & Co., Inc., Whitehouse Station, NJ, USA
ix
x Acknowledgments
Molecular Simulations, Inc., La Jolla, CA, USA
Pharmacia & Upjohn, Kalamazoo, MI, USA
Protein Engineering Network Centres of Excellence, Edmonton, Alberta
Schering-Plough Research Institute, Kenilworth, NJ, USA
Scios Inc., Palo Alto, CA, USA
Selectide Corporation, Tucson, AZ, USA
Silicon Graphics Inc., Calgary, Alberta
Vertex Pharmaceuticals Inc., Cambridge, MA, USA
CONTENTS
Plenary
I. The Aspartic Proteinases: An Historical Overview ....................... .
Tom L. Blundell, Kunchur Guruprasad, Armando Albert, Mark Williams,
Bancinyane L. Sibanda, and Venugopal Dhanaraj
Retroviral Aspartic Proteinases I
2. The Regulation of Sequential Processing of HIV-I Gag by the
Viral Protease ................................................ 15
Steve C. Pettit, Nijing Sheng, Radonna Tritch, Susan Erickson-Viitanen, and
Ronald Swanstrom
3. A Cellular Anti-Apoptosis Protein Is Cleaved by the HlV-1 Protease. . . . . . . . . . 27
Bruce D. Korant, Peter Strack, Michelle W. Frey, and Christopher J. Rizzo
4. Engineering Catalytically Defective Forms ofHlV Protease to Modulate Its
Activity ..................................................... 31
Charles S. Craik, Lilia M. Babe, Deborah Dauber, Fiona McPhee,
Jason Rose, and Ayce Dnal
5. The Aspartic Proteinase from Equine Infectious Anaemia Virus. . . . . . . . . . . . . . 41
D. J. Powell, D. Bur, A. Wlodawer, A. Gustchina, B. M. Dunn, and J. Kay
6. The Effect of Substrates on the Kinetics and the in Vivo Threshold Activity of
Mutant HlV-l Proteases ........................................ 47
Jacques Ermolieff, Xinli Lin, and Jordan Tang
7. A Comparison of gag-pol Precursor Cleavage in Naturally Arising HlV Variants 53
Gregory Bloom, Elena Perez, Shefal Parikh, John Kay, John Mills,
Maureen Goodenow, and Ben M. Dunn
8. X-Ray Crystallographic Studies of the Structure-Function Relationships of
HIV-I Protease ............................................... 59
Lin Hong, Cai Zhang, Jean A. Hartsuck, Steve Foundling, and Jordan Tang
xi