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Samenvatting Medical Biochemistry Deeltentamen 1
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Summary first partial exam of the course Medical Biochemistry and Pathophysiology; Medical Biochemistry, in the track Patient-centered Research.
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Medical Biochemistry and PathophysiologyLecture 1 – Enzymes and Enzyme Inhibitors
Spontaneous reaction → negative ΔG⁰
Gibbs energie → G = U + P*V – T*S
- U = energie
- P = druk
- V = expansie
- T = absolute temperatuur
- S = entropie
Je kunt niet energie maken → moet altijd worden opgenomen
➔ Wet van behoud van energie → eerste hoofdwet
Energie (U) kan worden opgenomen als → warmte (Q), arbeid (W) of in geïmporteerde stoffen
- Uimport = Q + W + Uin opgenomen stoffen
o Utoename = Q + W + Uin voedsel + Uproductie-consumptie
- Warmte kan vrij over het membraan bewegen → dus kan bij de cel naar binnen en naar buiten
Entropie → neiging tot chaos (hoe meer entropie, hoe meer vrijheidsgraden/chaos)
➔ Van lage naar hoge entropie (van het onwaarschijnlijke naar het waarschijnlijke)
- Er is maar 1 manier voor orde
- Er zijn heel veel manieren voor chaos
Paradox van Schrödinger
- Natuurkunde → van orde naar chaos
- Biologie → van chaos naar orde
Entropie exporteren naar buiten → ordenen in de cel terwijl de chaos buiten de cel groter wordt
Tweede hoofdwet → een systeem is in evenwicht als het zijn maximale entropie bereikt heeft
Exergoon (G-leverend) katabolisme is gekoppeld aan endergoon (G-benodigend) anabolisme
➔ De koppeling is de motor
- Deel van G komt terecht in product, en deel gaat verloren (zorgt wel voor de snelle reactie)
Als je iets wil maken in een cel wat energie kost, dan moet daar ATP aan gekoppeld worden
Gibbs vrije energie van een stof neemt toe bij hogere concentratie van die stof
➔ Hoe hogere concentratie van een molecuul, hoe minder vrijheidsgraden en dus meer orde
ΔG hangt af van
- De aard van de reactanten (substraat X en product P)
- De concentraties van de reactanten ([X] en [P])
De enthalpie van ATP helpt, maar een hogere concentratie
van ATP helpt ook bij het aandrijven van anabole reacties
Michaelis-Menten kinetics
Enzym (E) bindt substraat X → evenwicht wordt (soms) bereikt
- E + X ⇔ EX
- KD = Keq = KM = (([E]*[X])/[EX])eq
➔ Hoge KM, dan hoge [X] nodig om enzym half te verzadigen met X
➔ Als [X] = KM, dan helft enzym gereed te reageren
- Enzymfractie met gebonden substraat → (X/(KM+X))
Lage KM = hoge affiniteit
,Transition state of an enzyme → the transition state is the state corresponding to the highest energy along the
reaction coordinate. It has more free energy in comparison to the substrate or product; thus, it is the least
stable state. The specific form of the transition state depends on the mechanisms of the particular reaction
Prosthetic group → by attaching to a specific group of proteins called enzymes, prosthetic groups can make
enzymes active (turn them on) or increase their activity. Prosthetic groups that attach to enzymes are often
called cofactors or coenzymes because they help the enzyme to function
About 25% of the human genome encodes enzymes
Enzym klasse Biochemische functie
Oxido-reductase Enzymen die reacties katalyseren waarin een molecuul wordt geoxideerd, terwijl een
ander wordt gereduceerd. Deze enzymen worden veelal oxidase, oxigenase,
dehydrogenase of reductase genoemd.
Transferase Enzymen die een groep overzetten, zoals kinasen, die een fosfaat-groep overzetten.
Hydrolase Enzymen die een hydrolyse-reactie uitvoeren, waarbij een groep wordt afgesplitst. Zoals
proteasen, die peptide-bindingen tussen aminozuren splitsen, nucleasen, die de binding
tussen nucleotiden splitsen, fosfatasen, die fosfaatgroepen verwijderen, en ATPasen, die
ATP hydrolyseren.
Lyase (synthase) Enzymen die groepen verwijderen waardoor vaak een dubbele binding of een nieuwe
ring-structuur wordt gevormd. Zoals decarboxylasen, die een carboxyl-groep
verwijderen, adenylaat cyclase, dat ATP omzet in cyclisch-AMP, of ATP-citraat lyase, dat
citraat klieft tot acetyl-CoA en oxaloacetaat.
Isomerase Enzymen die een groep binnen het molecuul verschuiven, zoals fosfoglucomutase, dat
glucose-1-fosfaat omzet in glucose-6-fosfaat, of vice versa.
Ligase (synthetase) Enzymen die twee substraten aan elkaar zetten (ligeren) ten koste van ATP-hydrolyse.
Zoals pyruvaat carboxylase, dat bij pyruvaat een CO2 inbouwt ten koste van een ATP.
Enzyme-substrate reaction has two parameters
1. Interaction of enzyme with the substrate → binding ➔ Km
2. The bound substrate is being turned over → catalysis ➔ Vmax, kcat
Michaelis-Menten equation:
Vmax [S]
𝑣=
Km + [S]
Competitive inhibitors → bind reversibly to enzymes
➔ Substrate and inhibitor bind the same substrate
binding site to prevent substrate from binding
o Increased apparent Km, but Vmax unchanged
o Ibuprofen, statins, bortezomib, azoles, transition-state analogs (oseltamivir)
Noncompetitive inhibitors → bind reversibly to enzymes
➔ Bind at allosteric sites (locations other than its active site, inhibiting enzyme activity (no catalyzation))
o Decreased apparent Vmax, but Km unchanged
o Echinocandines
Irreversible inhibitors → bind irreversibly to enzymes
➔ Decreased Vmax: fewer active enzymes
o Acetylsalicylic acid (aspirin)
o Mechanism-based (‘suicide’) inhibitors
Allosteric enzymes → multidomain enzymes (a single subunit with regulatory and catalytic domains) or
multisubunit enzymes, such as dimers, trimers, and tetramers
➔ Do not obey simple Michaelis-Menten kinetics
,Allosteric inhibitors (small metabolites) → bind allosteric enzymes reversibly at an allosteric site (a site other
than the active site) and change the enzyme conformation from a more-active, relaxed (R) state to a less-active,
tense (T) state
All noncompetitive inhibitors are allosteric inhibitors, but not all allosteric inhibitors are noncompetitive
Suicide inhibitors → modified substrates that modify the active site of an enzyme (example on slide 12)
➔ Bind reversibly to the enzyme like substrates → catalytic mechanism generates chemically reactive
intermediate which inactivates the enzyme by a covalent modification which makes it irreversible
Cytochrome (CYP) enzymes → transfer electrons, using heme as its prosthetic group
- The iron ion of a cytochrome alternates between a reduced (+2) and an oxidized (+3) state during
electron transport
- Cytochrome P450 (CYP) is a family of cytochromes that absorbs light maximally at 450 nm when
complexed in vitro with exogenous carbon monoxide
The 57 different human CYP-enzymes are divided over 18 families
- CYP proteins can be divided into two groups:
o Those that metabolize xenobiotic (drugs, pollutants, agrochemicals)
o Those that participate in key biosynthetic pathways (biosynthesis of sterols or vitamin D)
The key difference between oxidases and oxygenases is that the oxidases are the enzymes that catalyze the
oxidation-reduction reactions by transferring the hydrogen from a substrate to oxygen, and thus, forming water
or hydrogen peroxide while, the oxygenases are the enzymes that catalyze direct incorporation of the oxygen
from the molecular oxygen (O2) to a substrate during the oxidation of a particular substrate
, Lecture 2 – Drug Development
Two approaches to drug discovery
1. Compound → physiological effect → molecular target
2. Molecular target → compound → physiological effect
Discovery by serendipity → combining coincidence with intelligence Alexander Fleming with penicillin
- Penicillin inhibits cross-linking of peptido-glycan chains, such that the bacterial cell wall weakens, and
bacterial cells lyse
- Ampicillin has a similar structure, but can bind better to another substrate
Sildenafil is an enzyme inhibitor → Viagra, discovered by accident
HAART → Highly Active Anti-Retroviral Therapy
➔ Combinations of different/multiple anti-retroviral drugs for the
treatment of AIDS
ADME properties of drugs
- Absorption
- Distribution
- Metabolism
- Excretion
Adsorption → depends on oral bioavailability, Lipinski’s Rules of 5
- Molecular weight <500
- Number of H-bond donors <5
- Number of H-bond acceptors (N and O) <10
- Partition coefficient, as log(P) <5
o log(P): log10 of the ratio of the drug concentration in octanol to the concentration in water
Distribution
- Hydrophobic compounds do not dissolve freely in the blood, but bind to abundant proteins such as
serum albumin
- Compounds distribute over various body fluids and tissues, called compartments
- Many compounds are unable to pass the blood-brain barrier
Metabolism → defense against xenobiotic (foreign) compounds
- Oxidation (phase 1 transformation)
- Conjugation (phase 2 transformation)
➔ Compounds become more water soluble and easier recognized as foreign compounds
Excretion → xenobiotic compounds are excreted from the body by two primary pathways
- Absorption through the kidneys and excretion in the urine
- Active transport by the liver into the bile and excretion into the intestines and the stool
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