Summary Class notes - Medical Biochemistry and Pathophysiology

Course
- Medical Biochemistry and Pathophysiology
- -
- 2019 - 2020
- Universiteit van Amsterdam
- Biomedische Wetenschappen
544 Flashcards & Notes
1 Students
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Summary - Class notes - Medical Biochemistry and Pathophysiology

  • 1567375200 Enzyme Inhibitors

  • Waar vindt katalyse plaats in het enzym?
    Active site
  • The specificity of an enzyme is due to the precise interaction of the substrate with the enzyme. This precision is a result of the intricate 3D structure of the enzyme protein.
  • Wat is een apoenzyme?
    Een enzym zonder zijn cofactor
  • Wat is holoenzyme?
    Een complete, katalytisch actieve enzym 

    Apoenzyme + cofactor = holoenzyme
  • Welke 2 groepen van cofactoren zijn er?
    1. Metalen
    2. Coenzymes (kleine organische moleculen)
         - Prosthetic groups (tightly bound coeenzymes)
         -  Cosubstrates (loosely associated coeenzymes)`
  • An enzyme cannot alter the equilibrium of a chemical reaction.
  • Hoe versnellen enzymen een reactie?
    Door de activatie energie te verlagen. Dus, door de formatie van de transitie staat te faciliteren
  • Waar halen enzymen de energie vandaan om de activatie-energie van een reactie te verlagen?
    Vrije energie komt vrij tijdens de formatie van een groot aantal zwakke interacties tussen het enzym en zijn substraat. Dit wordt ook wel binding energy genoemd. 
    De maximale hoeveelheid binding energy komt vrij tijdens de formatie van het enzym-substraat complex. 

    De energie die vrijkomt bij de interactie tussen het enzym en zijn substraat kan gezien worden als de verlaging van de activatie energie.
  • Waar hangt de Km van af?
    - Het substraat
    - Milieu (pH, temperatuur en ionic strength)
  • Waarom zit de normale concentratie van een substraat dicht bij de Km?
    Hierdoor kan het enzym significant actief zijn, maar ook gevoelig blijven voor veranderingen in het milieu. 

    (Als onder Km te weining activiteit en als boven te ongevoelig voor veranderingen)
  • Waarom volgen Allosteric enzymes niet de Michaelis-Menten curve?
    Allosteric enzymes hebben meerdere actives sites. De binding van een substraat aan een van de active sites kan de eigenschappen van een andere active site binnen hetzelfde enzym beinvloeden. De binding kan cooperatief worden: de binding van een substraat aan een van de active sites kan de binding van substraat aan een van de andere active sites fasciliteren (Sigmoide curve).
  • What is an irreversible inhibitor?
    An irreversible inhibitor dissociates very slowly from its target enzyme because it has become tightly bound to the enzyme (covalently & noncovalently) 

    *Penicillin
  • What is Reversible inhibition and which forms are there?
    Reversible inhibition is characterized by a rapid dissociation of the enzyme-inhibitor complex. 

    1. Competitive
    2. Uncompetitive
    3. Noncompetitive
    4. Mixed
  • What is competitive inhibition?
    The enzyme can either bind the substrate or the inhibitor, but not both. 
    The competitive inhibitor often resembles the substrate and binds to the active site of the enzyme, leaving it blocked for the substrate.

    A competitive inhibitor diminishes the rate of catalysis by reducing the proportion of enzyme molecules bound to a substrate.

    Competitive inhibition can be relieved by increasing the substrate concentration. Then the substrate successfully competes with the inhibitor for the active site.
  • What is uncompetitive inhibition?
    Uncompetitive inhibition is substrate-dependent inhibition; the inhibitor only binds to the enzyme-substrate complex.

    Binds only to ES-complex

    * cannot be overcome by the addition of more substrate
  • What is noncompetitive inhibition?
    In noncompetitive inhibition both the inhibitor and substrate can bind simultaneously to an enzyme at different binding site. 

    A noncompetitive inhibitor acts by decreasing the concentration of functional enzyme rather than by diminishing the proportion of enzyme molecules that are bound to the substrate.

    Decreases the turnover number.   
  • What is mixed inhibition?
    This is when a single inhibitor both hinders the binding of substrate and decreases the turnover number of the enzymes.
  • What happens with the Km and Vmax when a competitive inhibitor is used?
    Km is increased (more substrate is needed to obtain the same reaction rate) and the Vmax stays the same.
  • What is the effect of uncompetitive inhibtion on the Km and Vmax?
    Km and Vmax will be lower.
    Km is lower because the inhibitor binds to ES to form ESI, depleting ES.
  • What happens with Km and Vmax when a noncompetitive inhibitor is used?
    Vmax is decreased and Km stays unchanged.
  • How does penicillin work?
    Penicillin is an antibiotic and therefor kills bacteria. Penicillin does this by inhibiting Glycopeptide transpeptidase which is responsible for the formation of the cross-links that make the peptidoglycan stable. Without these cross-links the cell wall becomes unstable and the cell will burst because of it's high osmotic pressure. 

    Penicillin mimics the natural substrate transpeptidase usually binds, it has the same D-Ala-D-Ala moiety as the normal substrate. Normally, transpeptidase forms a acyl intermediate with the D-alanine residue after which the intermediate interacts with the amino group of the terminal glycine in another peptide to form a cross-link. However, when penicillin binds, it forms a covalent bond with a serine residue at the active site of the enzyme. The penicilloyl-enzyme cannot react further; the transpeptidase is irreversibly inhibited and cell-wall synthesis cannot take place. 

    Because the peptidase participates in its own inactivation, penicillin acts as a suicide inhibitor.
  • High Vmax --> high turnover
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How is the nucleus accumbens (NAc) involved in glucose metabolism?
NAc is involved in rating how much we like a certain food (hedonic value) and also how much we want that food (motivation). It also contains glucose sensing neurons, and when stimulated, blood glucose levels rise. 

Dopamine system within NAc!
To which brain parts has the ARC projections to?
PVN, LH and VMH

LH: 'hunger center
VHM: saturation center
How is dopamine linked to glucose metabolism?
- Dopamine is the key neurotransmitter for reward processes
- Produced in ventral tegmental area and substantia nigra 
- 5 receptors: D1, D2, D3, D4, D5

The metabolism of glucose release dopamine, so the breakdown is actually needed for the reward system.
Mice: huge preference flavour conditioned with glucose vs flavour linked to non-metabolized glucose. 

* Obese subjects have reduced dopamine binding.
How does the melanocortin (MC) system work?
There is competition for the MC4R receptor by AgRP and alpha MSH
- Md4R shows constitutive activity, thus in suppresses food intake 
(when there is no MC4R there is no suppression, resulting in an obese phenotype)
- AgRP inhibits MC4R while alpha MSH stimulates MC4R.
What do POMC neurons do?
- POMC = Pro-opiomelanocortin
- alpha MSH is derived from POMC
- Located in hypothalamus, in the Arcuate Nucleus (Arc)
- Decreases food intake 
- Are glucose excited (GE) neurons    
What do NPY/AgRP neurons do?
- Are located in the hypothalamus, in the Arcuate Nucleus (Arc), which is close to the blood brain barrier.
- NPY = Neuropeptide Y
AgRP = Agouti related peptide
- Increase food intake 
- Are glucose inhibited (GI) neurons  
What does an glucose-sensing cell need?
1. Glucose transporters (Sodium glucose linked cotransporters)
2. Energy sensing enzymes
3. Transmembrane channels sensitive to changes in energy status
Which brain centers express glucose sensing neurons?
Hypothalamus, striatum & brainstem
What are the types of glucose sensing neurons?
- Glucose inhibited (GI)
- Glucose excited (GE)
What is the difference between homeostatic and hedonic?
- Homeostatic: eating to maintain bodily functions
Regulated by hypothalamus
- Hedonic: eating because you want something  
Regulated by striatum