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Mitochondrion

Peroxisome

Alcohol Metabolism

Eric Niederhoffer

SIU-SOM

EtOH

Acetaldehyde

Acetate

Cytosol

ERADH

NAD+

NADHCAT

H2O2

H2O

AlDHNAD+

NADH

MEOSNADP+NADPH

O2P450

Extra-hepatic tissue

Oh my!Now what?

Pyrazol

Disulfiram(antabuse)

Chlorpropamide(diabetes)

Aminotriazole

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Pathway PerturbationsGlc

Ala

ALT

Malate MDHNADHNADH

Malate

PEPCK

G6P GKF6P

F16BPPFK

PEP

PyrPK

NADH

NADH

Malate

SucFum

PDHAcetyl CoA

CitICit

Mitochondrion

Cytosol

NADH

NADH

PCOAA

AspASTOAA

MDHNAD+

OAAMDHNAD+

KGIDHNAD+

Lactate LDHNAD+

S CoAKGDHNAD

+

G6Pase

F16BPase

NADH

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Malate-Aspartate Shuttle(liver, kidney, heart)

IMS Matrix

GT

OAA

NADH

ASTGlu

KG

Mal

NAD+

MDH

Asp

ASTGlu

KG

OAA

NADH

NAD+

MDH

CI

MTMal

Asp

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Glycerol-3-PhosphateShuttle

(skeletal muscle, brain)

NADH DHAP

NAD+G3P

IMS Matrix

G3PDH

Q CIIIFADH2

FAD

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Review Questions

How is ethanol detoxified(enzymes, cofactors, products,location)?

Which metabolic pathways areaffected by alcohol-derived NADH(enzymes, metabolites)?

How does the cell process NADH?

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Descoberta docitocrmio P 450

1955 artigo de Alxerod

Detoxication of drugs and other foreign

compounds by liver microsomes.BRODIE BB, AXELROD J, COOPER JR,

GAUDETTE L, LA DU BN, MITOMA C,

UDENFRIEND S.

Science. 1955 Apr 22;121(3147):603-4.

1958 evidencia da formao docomplexo com CO

1964

1985 estrutura 3D de um citocrmio dePseudomonas putida

http://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/14372965?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

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The most common reaction catalysed bycytochrome P450 isa monooxygenase reaction,

e.g. insertion of one atom of oxygen into an

organic substrate (RH)while the other oxygen atom is reduced towater:

RH + O2+ 2H++ 2eROH + H2O

Cytochrome P450(abbreviated CYP, P450,

infrequently CYP450) is a very large and diversesuperfamily of hemoproteinsfound in alldomains of life.

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O sistema citocrmio P-450 :

relevncia no metabolismo e comobioremediador

Cytochrome P450(abbreviated CYP, P450,

infrequently CYP450) is a very large and diversesuperfamily of hemoproteinsfound in alldomains of life.

The most common reaction catalysed by cytochrome

P450 isa monooxygenase reaction,

e.g. insertion of one atom of oxygen into an organicsubstrate (RH)while the other oxygen atom is reduced to water:

RH + O2+ 2H++ 2eROH + H2O

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The name cytochrome P450isderived from the fact that theseare colored ('chrome') cellular('cyto') proteins, with a "pigment at450 nm", so named for the

characteristic Soret peak

formed by absorbance of light atwavelengths near 450 nm when theheme iron is reduced and

complexed to carbon monoxide

Citocromio

P 450

educed

+

Carbon

monoxide

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http://upload.wikimedia.org/wikipedia/commons/3/39/P450cycle.svg

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There are over 30 human P-450 isoenzymesystems that have been identified to date.The major ones responsible for drugmetabolism are the CYP1A2, CYP2A6, CYP2B6,

CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6,CYP2E1, CYP3A4 and the CYP3A5-7.

Estrutura 3D doCitocrmio P 450 oxidase

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Componentes do sistema efuncionamento

1. oxidase2. Na sntese de grupos hidroxilo3. Na sntese de grupos carboxilos

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Estrutura 3D doCitocrmio P 450

oxidase

Estrutura 3D doCitocrmio P 450

oxidase

http://upload.wikimedia.org/wikipedia/commons/5/56/CytP450Oxidase-1OG2.png

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Uma protena demembrana

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AlmadaNegreiros