Highlights of the meeting

15th International Symposiumon Cytochrome P450

 International Symposia on Cytochrome P450

Year               Place                                         Lead organizer

1976                Primosten, Yugoslavia              Sinisa Maricic (Klaus Ruckpaul)1978                Eberswalde, GDR                     Klaus Ruckpaul 1980                Saltsjöbaden, Sweden               Jan-Åke Gustafsson1982                Kuopio, Finland                          Osmo Hänninen1985                Budapest, Hungary                   Laszlo Vereczkey1988             Vienna, Austria                           Inge Schuster 1991                Moscow, Russia                         Alexander Archakov1993               Lisbon, Portugal                         Maria C. Lechner1995             Zürich, Switzerland                     Wolf Woggon1997               San Francisco, USA                   John Dawson 1999                Sendai, Japan      Yoshiaki Fujii-Kuriyama &

Yuzuru  Ishimura2001                La Grande Motte, France           Reinhard Lange2003                Prague, Czech Republic             Pavel Anzenbacher2005                Dallas, USA                        Julian Peterson & Sandra Graham 2007               Bled, Slovenia                            Damjana Rozman2009                Bankoku Shinmryokan, Japan    Hirofumi Shoun2011                Manchester, UK                         Andrew Munro

List of sessions

Functional genomics

P450s and nanotechnology

P450 structure and function

Transcriptional regulation

Heme thiolate proteins

P450s in metabolism and drug discovery

New mechanisms of P450 reaction

P450 cross talks and interactions

Post-transcriptional events

Biophysical methods

Biotechnology and bioinformatics

Novel P450-partner interactions

List of sessions

Functional genomics

P450s and nanotechnology

P450 structure and function

Transcriptional regulation

Heme thiolate proteins

P450s in metabolism and drug discovery

New mechanisms of P450 reaction

P450 cross talks and interactions

Post-transcriptional events

Biophysical methods

Biotechnology and bioinformatics

Novel P450-partner interactions

What was new in Bled 2007?

1) Many P450 structures: flexibility/adaptation to different ligands (SF-1 also flexible)

Sheds new light on biophysical methods like ITC, RR,

high pressure Be cautious when applying radiation on redox

proteins2) Nanobiotechnological approaches: nanodiscs to P450 music

3) Complicated kinetic in some P450 systems

4) New reaction types

5) The first P450 with 2 independent active sites and two reactions catalysed

6) Heme thiolate proteins: e.g. heme sensing

7) Diversity of ET partners and complexes

P450

RH + O2

FdR

FdxNADH + H+

NAD+

A

R-OH + H2O

Inner mitochondrial membrane

P450

RH + O2

R-OH + H2O

FdR

FdxNADPH + H+

NADP+

B

Matrix

C

ER membrane

P450P450

NADPH + H+

NADP+

CPR

RH + O2

R-OH + H2O

Cytoplasm

P450cinFdR

FldxNAD(P)H + H+

NAD(P)+

D

RH + O2

R-OH + H2O

P450Fdx

Pyruvat

CO2

CoA Acetyl-CoA

OFOR

E

RH + O2

R-OH + H2O

Fdx

P450NADP+

NADPH + H+

FdR

FRH + O2

R-OH + H2O

Fldx

P450NAD(P)+

NAD(P)H + H+

FdR

GRH + O2

R-OH + H2O

P450

NADP+

NAD(P)H + H+

PFOR

H

RH + O2

R-OH + H2O

P450

NADPH + H+

NADP+

CPR

RH + O2

R-OH + H2O

P450

I

NADH + H+

NAD+

RH + O2

R-OH + H2O

P450nor

J

PGH2

TxA2

P450TxA

K

F. Hannemann et al.BBA 1770 (2007) 330–344

Biological variations of electron transport chains

8) Regulation: interactions between different pathways phenobarbital induction, sex-dependence - drug – cholesterol biosynthesis - drug – basic energy metabolism - drug – lipid metablism Need for application of systems biology

- regulation by mikroRNAs and DNA methylation New regulatory level

6) Heme thiolate proteins: e.g. heme sensing

7) Diversity of ET partners and complexes

9) P450s as tumor markers new drug targets

Activation of prodrugs in the tumor cell

Sterols

CYP51 CYP7A1

CYP27A1 CYP46CYP39

Vitamin D

CYP27 A1, B1, C1 CYP24

Steroid(hormone)s

CYP11 A1,B CYP17 CYP19 CYP21A2CYP7B1

CYP26A1,B1,C1

Arachidonic acid

CYP5A1 CYP8 A1,B1

NO synthase

EndogenEndogenous ous SubstrateSubstratess

CYP3A (4, 5, 7, 43)

CYP2 A(6,7,13),B6,C(8,9,18,19)D6,E1,F1,J2,R1,S1,U1,W1

CYP1 A1, A2, B1

XenobiotiXenobioticscs

CYP4 A(11,22),B1,

F(2,3,8,12,22), V2,X1,Z1

CC YY PP

Retinoic acid

From: Inge Schuster

Sterols

CYP51 CYP7A1

CYP27A1 CYP46CYP39

Vitamin D

CYP27 A1, B1, C1 CYP24

Steroid(hormone)s

CYP11 A1,B CYP17 CYP19 CYP21A2CYP7B1

CYP26A1,B1,C1

Arachidonic acid

CYP5A1 CYP8 A1,B1

NO synthase

EndogenEndogenous ous SubstrateSubstratess

CYP3A (4, 5, 7, 43)

CYP2 A(6,7,13),B6,C(8,9,18,19)D6,E1,F1,J2,R1,S1,U1,W1

CYP1 A1, A2, B1

XenobiotiXenobioticscs

CYP4 A(11,22),B1,

F(2,3,8,12,22), V2,X1,Z1

CC YY PP

Retinoic acid

From: Inge Schuster

8) P450s as tumor markers new drug targets Activation of prodrugs in the tumor cell

9) Role in disease: Fungal resistance, breast cancer treatment (new targets by understanding regulation)

10) Engineering of P450s for biotechnological application- P450BM-3 approaches non-heme monooxygenases in their propane and ethan hydroxylation ability- Use of P450 for the phytoremediation of explosives- use of P450 for the production of the anti-malaria drug artemisinin

The high(est)light of the Conference

Open questions – new challenges

1) Oxygen activation mechansim in various systems2) 3D structure of mitochondrial P450s

Will solid-state NMR help us a lot?3) Interaction, ET, gating?4) 3D structures of ET complexes with P450 or of P450 complexes with other interacting proteins 5) Function of all 57 human P450s6) Role in neurobiology (CYP46, others?)7) Role in cardiovascular diseases8) Personalized drug therapy9) P450s as drug targets10)Sustainable biotechnological application of P450s

Highlights?

•broad and sturdy side (wall)•tusk (spear)•trunk (snake)•knee (tree)•Ear (fan)•tail (rope)

Thank you, Damjana!

Thanks to all members of the Organizing Committee!