biotransformation
DESCRIPTION
general biotransformation reactions occurring in organisms...TRANSCRIPT
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Biotransformation Presented by
PREETHI. G. UI sem MSC biotechnology
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BIOTRANSFORMATION
Chemical alteration of a substance within the body, as by the action of enzymes
Vital to survival
Key in defense mechanism….
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UPTAKE
ORGAN
EXCRETION
ORGAN
UPTAKE
EXCRETION
Primarily biotransformation makeslipophilic compounds more hydrophilic
UPTAKE
EXCRETION
BIOTRANS-FORMATION
Uptake and excretion of hydrophilic and lipophilic compounds
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REACTIONS
PHASE I : modification
PHASE II : conjugation
PHASE III : transport
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A small polar group is either exposed on the toxicant or added to the toxicant…
Oxidation
Reduction
Hydrolysis
Acetylation
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PHASE I REACTION
OXIDATION substrate loses electrons
addition of oxygen, dehydrogenation, or
simply transfer of electrons…
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alcohol dehydrogenation aldehyde dehydrogenation alkyl/acyclic hydroxylation aromatic hydroxylation deamination desulfuration N-dealkylation N-hydroxylation N-oxidation O-dealkylation sulphoxidation
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Aliphatic hydroxylation
Aromatic hydroxylation
R R OH
R - CH CH - R’ R - CH - CH - R’
Epoxidation
O
N-, O-, or S-dealkylation
R - (N, O, S) - CH3
H
N - hydroxylation
Deamination
R - C - H + NH3
O
OO
R - NH - C – CH3 R - NOH - C – CH3
R - C - H R - C - OH R - C - H + HX
OX X
H H
R - S - R’ R - S - R’
Sulphur oxidation
S
R1R2P - X R1R2P - X + S
O
De-sulphurnation
Oxidative dehalogenation
R - CH2 – CH2 – CH3 R – CH2 – CHOH – CH3
R – (NH2, OH, SH) + CH2O
R – CH2 – NH2
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PHASE I REACTION
REDUCTION Substrate gains electrons Occurs when oxygen content is low Common reaction
○ azo reduction ○ dehalogenation ○ disulfide reduction ○ nitro reduction ○ N-oxide reduction ○ sulfoxide reduction
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PHASE I REACTION
HYDROLYSIS Addition of water splits the molecule into
two fragments or smaller molecules
-OH gp to one fragment and –H to other
Eg : Larger chemicals such as esters, amines, hydrazines, and carbamates
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Conjugation
Endogenous substance is added to the reactive site of the Phase I metabolite
more water-soluble
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TYPE I Methylation
Glucuronidation
Sulfation
Acetylation
TYPE II Peptide conjugation
Glutathione conjugation
Glycosylation
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glucuronide conjugation
sulfate conjugation
acetylation
amino acid conjugation
glutathione conjugation
methylation
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COFACTORSCOFACTORSType 1- Reactive/ Activated
Cofactor a)UDP- Glucuronic acid
b)PAPS
c)Acetyl CoA
d)SAM
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Type 2- Reactive Xenobiotic a)Glutathione
b)Aminoacids(glycine,glutamine,
taurine)
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Glucuronosyltransferase
Sulfotransferase
Glutathione-S-transferase
Acetyltransferase
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GLUCURONIDE CONJUGATION glucuronic acid from glucose Sites involve substrates having O2, N2 or
S bonds Includes xenobiotics as well as
endogenous substances Reduces toxicity..(sometimes produce
carcinogenic substances) Excreted: kidney or bile depending on
conjugate size
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GLUCURONIDE CONJUGATION
R – OH + UDPO
HO
O
OH
OH
COOH
Glucuronyltransferase O
HO
O
OH
OH
COOH
R + UDP
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SULPHATE CONJUGATION Decreases toxicity readily excreted by urine Sulphotransferase PAPS limits the pathway
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SULFATE CONJUGATION
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glucuronidation or sulfation can conjugate the same xenobiotics
Primary, secondary, phenols, catechols, N-oxides, amines undergo this…
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GLUTATHIONE CONJUGATION Conjugate loses glutamic acid and glycine
Cysteine is N-acetylated to give stable mercapturic acid derivatives
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N
O
H
O
H
N
S
H
O
N
O
O
H H
OH
H
H+
+
N
OO
O
H H
O
H
H
N
O
S
H H
O
H
N
O
HH
O
H
Glutamicacid
Cysteine
GlycineGlutathione
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ACETYLATION the water solubility of parent molecule
and their excretion Masks the functional group of parent
from participating in conjugations Acetyl transferases Aromatic amines or hydrazine group to
amides or hydrazides
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MethylationMakes slightly less solubleMasks available functional groupsTypes
O- methylation
N- methylation
S- methylation
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PHASE II REACTIONS
Aminoacid conjugation
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GENETICSNfr2- nuclear factor erythroid derived
Inactive oxidative stress active
CP nucleus
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Additional conjugation reaction
ABC family (MDR proteins)
Conjugates and their metabolites can be excreted from cells
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Anionic transporter : OATP1B1/SLCO1B1
Cationic transporters : OATP1B3/SLCO1B3
ABC transporters: P glycoprotein
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ENZYMES
ENZYMESmicrosomal…. Phase I and glucuronidation
enzymesCytosolic enzymes….phase II and oxidation
and reductionMitochondrial, nuclei and lysosomes contain
a little transforming activity….
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MICROSOMALPhase I reactions
– Most oxidation and reduction
– Some hydrolysis
Phase II reactions– ONLY Glucuronide
conjugation• Inducible
– Drugs, diet, etc. SER
NONMICROSOMALPhase I reactions
– Most hydrolysis– Some oxidation and
reductionPhase II reactions
ALL except Glucuronide conjugation
• Not inducible CP, MT etc
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ENZYMES
High molecular weight proteins..
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CYP
FLAVIN MONOOXYGENASES
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CYTOCHROME P450 ENZYME SYSTEM
Mixed function oxidase Commonly in microsomes Important in plant terpenoid biosynthesis In phase I reactions Contains 2 enz NADPH CYP reductase and
cyp 450
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CYTOCHROME P450 ENZYME SYSTEMCYTOCHROME P450 ENZYME SYSTEM
superfamily of heme-dependent proteins
expressed in mammals mainly in the liver, with lower levels of expression in the small intestine, lungs, kidneys, brain and placenta
In man, to date 57 different P450 isoforms have been identified, which were assigned to 18 families and 43 subfamilies based on their protein sequences
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REDUCTASE
P-450P-450
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TYPES
Microsomal P450 systems: electrons are transferred from NADPH via cytochrome P450 reductase.
Mitochondrial P450 systems: employ adrenodoxin reductase and adrenodoxin to transfer electrons from NADPH to P450.
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Bacterial P450 systems: employ a ferredoxin reductase and a ferredoxin
CYB5R/cyb5/P450 systems: both electrons required by the CYP come from cytochrome b5.
FMN/Fd/P450 systems: originally found in Rhodococcus sp. in which a FMN-domain-containing reductase is fused to the CYP.
P450 only systems, which do not require external reducing power. Notable ones include CYP5 (thromboxane synthase), CYP8(prostacyclin synthase), and CYP74A (allene oxide synthase).
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CYP2D6
Cyto proteinsColoured
450nm
FamiliesDesignated by numerals
SubfamiliesDesignated by capital letters
Iso enzymesDesignated by numerals
40-55% aa seq homology>55% seq homology
40% seq homologyNOMENCLATURE
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CYTOCHROME P 450 ENZYME ACTION
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HC(inducer)
Ah receptor-hsp90
HC
P450 mRNAP450 protein
• Bioactivation• Detoxification
Toxicity
Elimination
Cell
HC-AhR
hsp90
HC-AhR
XRE
P450 gen
Nucleus
HC: Hydrocarbon (inducer)XRC: Regulator gene (stimulates transcription of P-450 gene)
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P450 family Function
CYP1, CYP2, CYP3 Metabolism of drugs and xenobiotics
CYP4, CYP5, CYP8
Fatty acids hydroxylation, biosynthesis of prostaglandins, prostacyclins and thromboxanes
CYP7, CYP11, CYP17, CYP19 (=steroid aromatase), CYP21, CYP24, CYP27, CYP39, CYP46, CYP51 Biosynthesis and metabolism of cholesterol, steroid
hormones and bile acids
CYP26 Retinoic acid hydroxylation
CYP20 Unknown
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FLAVIN MONO OXYGENASE
Microsomal enzyme
mixed function amine oxidase
Cofactors: NADPH, molecular O₂
Do not contain heme
Broad specificity
Nicotine detoxification
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OTHER ENZYMES
Monoamine oxidases- breakdown of neurotransmitters and antidepressant drugs
Alcohol and aldehyde dehydrogenases
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BIOTRANSFORMATION SITES
Liver Lung Kidney Intestine Gut Skin Gonads
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ENZYME CONTAINING CELLS IN VARIOUS ORGANS
Liver Kidney Lung
Intestine
Skin Testes
Parenchymal cells
Proximal tubular cells
Clara cells, type II alveolar cells
Mucosa lining cells, enterocytes
Epithelial cells
Seminiferous tubules, sertoli cells
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MICROSOMAL FRACTION
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PHASES OF BIOTRANSFORMATION
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IMPORTANCE
Drug metabolism Factor in multidrug resistance Cancer chemo therapy Environmental science- bioremediation or
persistence in environment
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BIOTRANSFORMATION OF ALCOHOL
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INTESTINAL FLORA AND BIOTRANSFORMATION
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DRUG METABOLISM
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BIOTRANSFORMATION IN MICROORGANISMS
elimination of wide range of pollutant and waste removal of contaminants by degrade/convert such
compounds. adapt and become quite rapidly selected to
xenobiotic compounds introduced into the environment, mainly via the usage of the compound as carbon, energy or nitrogen source.
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CYP IN MICROORGANISMS
Cyt P450cam (CYP101): first cytP450 3D protein structure solved by X-ray crystallography
part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from putidaredoxin, a 2Fe-2S cluster-containing protein cofactor.
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Cytochrome P450 eryF (CYP107A1) originally from the actinomycete bacterium Saccharopolyspora erythraea is responsible for the biosynthesis of the antibiotic erythromycin by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
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Cyt P450 BM3 (CYP102A1) from the soil bacterium Bacillus megaterium catalyzes the NADPH-dependent hydroxylation of several long-chain fatty acids at the ω–1 through ω–3 positions..
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CytP450 119 (CYP119) isolated from the thermophillic archea Sulfolobus acidocaldarius has been used in a variety of mechanistic studies
function at high temperatures, they tend to function more slowly at room temperature (if at all) and are therefore excellent mechanistic models.
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IN FUNGI
The commonly used azole class antifungal drugs work by inhibition of the fungal CYP 14α-demethylase. This interrupts the conversion of lanosterol to ergosterol, a component of the fungal cell membrane.
Cunninghamella elegans is a candidate for use as a model for mammalian drug metabolism
Significant research is going on…
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BIOTRANSFORMATION IN PLANTS
o large amounts of peroxidases in plants
o small amounts of CYP in plant tissues
o a low substrate specificity of plant peroxidases as compared to the high
specificity of the plant CYP
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o a wide range of action of plant peroxidases o the similarity of in vivo metabolites of several
xenobiotics in plants to those formed in vitro by peroxidases rather than to those resulting from cytochrome P-450-dependent in vitro reactions
o high affinities of peroxidases to exogenous substrates
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o peroxidases are located in all parts of plant cells, the plant CYP are located in the microsomal fraction only.
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In plants…. Transformation occurs in pesticide and heavy
metals Using plant cell cultures
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CO-METABOLISM Multistep process Not used for energy production Not a constitutive element of organism Secondary substrate metabolism
Enzyme A ----------> Enzyme B -------------> Enzyme C
Substrate A ----------> Product B ------------> Product C
Substrate Ax-----------> Product Bx [not metabolized by enzyme C]
Substrate Ax is "sufficiently similar" to Substrate A that Enzyme A can transform it to Bx, but Bx is "sufficiently different" to B so as to prevent further metabolism by Enzyme C.
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REACTIONS INVOLVE…
OXIDATIONREDUCTION HYDROLYSISCONJUGATION
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OTHER ENZYMES INVOLVED
Peroxidases Phenolases Other oxidoreductases Hydrolytic enzymes
Polymerisation of various anilines and phenolsUsually decreases toxicity
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HYDROLYTIC ENZYMES
Metabolise substrates containing amide, carbamate or ester functional group
Extracellular Anaerobic or aerobic
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ESTER HYDROLYSIS
Esterases, lipases, proteases GLY-X-SER-X-GLY The SER acts as a nucleophile, enabling
ester bond cleavage Increases absorption and selectivity Ester bond metabolised to form acid (more
toxic) which is desterified
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Amide hydrolysis
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ROLE OF GST AND GSH IN PLANTS
Metabolism of secondary products(cinnamic acid, anthocyanins)
Regulation and transport of both endo and exogenous compounds
Protection against oxidative stress Involved by vacuoles
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PHASE III
Additional conjugation
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NON SPECIFIC REACTIONS
NitroreductionNitroreduction HydroxylationsHydroxylations GlucosylationGlucosylation Oxido-reductions between alcohols Oxido-reductions between alcohols
and ketonesand ketones HydrolysisHydrolysis EpoxidationEpoxidation Reductions of carbonyl groupsReductions of carbonyl groups Reduction of C–C double bondReduction of C–C double bond
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REACTION Hydroxylation
Nitroreduction Glucosylation
Oxido reductions Hydrolysis
EXAMPLE Warfarin to alcohol(C.roseus)
TNT to ADNT(D.inoxia) Butyric acid to 6- o butyryl-
glucose(N.plumbaginifolia
Alcohols to ketones(N.tabaccum) 1-phenyl ethyl acetate to R
alcohols(Spirodela oligorrhiza)
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Epoxidation
Reduction of carbonyl group
Reduction of C=CC=C
(−)-(4R)-isopiperitinone to (−)-7-hydroxyisopiperitonone(Menthapiperita)
Ketones and aldehydes to alcohols(N.sylvestris)
Carvone reduction(Astasia longa)
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Major conjugation reactions in plants and animals
Glucuronide formation prevalent in vertebrates Glycoside formation prevalent in plants and insects Mercapturates animals only Cysteine conjugation plants and animals Gycine conjugation plants and animals Other aminoacid conjugation plants and animals Sulphate conjugation prevalent in animals rare in plant O and S methylation animals and plants Thiocyanate formation animals and plants N- acetylation animals and plants
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IN HUMAN Mainly haemoglobin biotransformation
Detoxification
Drug metabolism
Transformation of endogenous molecules
hormone synthesis and breakdown
cholesterol synthesis
vitamin D metabolism..
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CYP IN HUMANS
The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes.
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PROCESSING OF PROCARCINOGEN BY BIOTRANSFORMING ENZYMES
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AGE
GENDER
GENETIC VARIABILITY
POOR NUTRITION AND DISEASES
DOSE LEVELS
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SYNDROMES ASSOCIATED…
GILBERTS SYNDROMEReduced activity of glucuronyl transferase
Hyper bilirubinemia
Develops jaundice CRIGLER-NAJJAR SYNDROME
Autosomal recessive disorder
No UDP glucuronosyltransferase
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CROHN’S DISEASEAn imbalance between toxic compounds
and detoxifying substances on the luminal side of the gut
inflammation of the intestinal mucosa ANTLEY-BIXLER SYNDROME
Abnormal production of cholesterol
Mutation in POR gene
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APPLICATIONS
Therapeutic drug monitoring Cancer chemo therapy and drug metabolism Oil degradation in marine systems Natural attenuation and bioremediation Waste biotreatment Aerobic and anaerobic degradation of organic
pollutants Transformation of specific substrates into products of
interest in vitro
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REFERENCE
http://www.eoearth.org/article/Biotransformation?topic=58074 profiles.nlm.nih.gov/ps/access/CCAAOR.pdf www.slideshare.net/shishirkawde/biotransformation-10417087 www.eolss.net/sample-chapters/c17/e6-58-04-06.pdf www.ncbi.nlm.nih.gov/pubmed/3116933 ingentaconnect.com RK Venisetty, V Ciddi - Current pharmaceutical
biotechnology, 2003 web.squ.edu.om/med-Lib/MED_CD/E_CDs/.../020160r00.HTM www.eoearth.org/article/Biotransformation
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