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Flashcards in Enzymes I and II Deck (44):
1

2 functions of enzymes

1. Proteins that control the kind of chemical reactions that can occur 2. Control the rate of reactions

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Enzyme structure and domains

Have primary, secondary, and tertiary structure. Different domains with different functions including prodomain, catalytic domain, substrate-binding domain, transmembrane domain

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Substrate

Molecule that the enzyme acts upon

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Substrate-binding site

Specifically recognizes a particular substate (or limited number of substrates). Reason why enzymes show high specificity.

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Catalytic site

Contains residues that catalyze the reaction by acting on the substrate (often helped by cofactor)

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Active site

Substrate-binding site + catalytic site

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3 ways to categorize enzyme inhibitors

1. Reversible vs. irreversible 2. Competitive vs. non-competitive 3. Selective vs. non-selective

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Exogenous inhibitors

Administered to the body

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Endogenous inhibitors

Present in the body, naturally occurring

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Zymogen

Also called a pro-enzyme. Inactive form of the enzyme which requires activation (often by another enzyme).

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6 types of enzymes

1. Oxioreductases 2. Transferases 3. Hydrolases 4. Isomerases 5. Lyases 6. Ligases

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Oxioreductases

Transfer hydrogen or oxygen from one substrate to another--redox reactions (e.g. oxidases)

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Transferases

Transfer functional groups from one substrate to another (e.g. kinases)

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Hydrolases

Catalyze hydrolysis of a substrate--add water across a bond (e.g. digestive enzymes)

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Isomerases

Change the molecular form (isomer) of a substrate

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Lyases

Remove or add a group to the substrate in a non-hydrolytical way--add/remove water, ammonia, carbon dioxide across double bond (e.g. carboxylases)

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Ligases

Join 2 molecules through formation of bonds between C and O, S, N (e.g. citric acid synthetase) using ATP

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4 ways to regulate enzyme activity

1. Substrate availability 2. Enzyme availability 3. Enzyme activation 4. Enzyme inhibitors

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Substrate availability

Amount of substrate determines rate of reaction. Location of the substrate and conformation of the substrate also important.

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Enzyme availability

Transcriptional and translational up or down regulation, de novo synthesis (small molecules to large ones)

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Amyloid precursor protein (APP)

Processed by secretases. Mutant type in Alzheimer's 1000x better substrate for _-secretase than wild type. _-cleavage and _-cleavage lead to plaques but _-cleavage pathway does not. Blocking _-secretase could prevent plaques.

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5 pillars of inflammation

1. Heat 2. Redness 3. Swelling 4. Pain 5. Loss of function

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Prostaglandins

Key mediators of inflammation

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Cyclooxygenase

Cox: enzyme that turns arachidonic acid into prostaglandin H. Two types: Cox-1 and Cox-2

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Cox-1

Constitutively expressed.

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Cox-2

Induced by inflammation.

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Cox inhibitors

Potent anti-inflammatory drugs. General Cox inhibitors have GI side effects, but not Cox-2 inhibitors.

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Trypsinogen

Zymogen of trypsin secreted by pancreas. Activated in the bowl by enzyme called enterokinase.

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Enterokinase

Enzyme which activates trypsinogen in the bowl

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Trypsin

Derived from pancreas. When active attacks other zymogens and result in digestion of peptide bonds in food proteins

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Pancreatitis

Inflammation of the pancreas. Excess active trypsin over endogenous inhibitor which results in massive activation of these enzymes in the pancreas. Severe pain, vomiting, abdominal rigidity, fever, shock. High lethality.

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Proteases

Hydrolases which cleave peptide bonds in proteins. Involved in maturation of viral proteins, digestion, intracellular protein degredation, controlling biological processes (blood pressure, clotting cascade, immune response, apoptosis), remodeling ECM.

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4 major classes of proteases

Grouped by mechanism used to form nucleophile that attacks peptide bond 1. Serine proteases (e.g. trypsin) 2. Aspartyl proteases (e.g. HIV protease) 3. Metalloproteases (e.g. MMPs) 4. cysteine proteases (e.g. caspases)

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Metalloproteases

Use a metal (Zinc) to coordinate and activate attacking water molecule

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Endochondral ossification

Vessels grow into the bone, cavity forms, and ossification results in degraded cartilage (Arthritis)

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MMP

Matrix metalloproteases

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3 examples of remodeling using metalloproteases

1. ECM remodeling as part of normal growth/development 2. Pathological remodeling during diseases like arthritis 3. Cancer cells use proteases to invade tissues

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3 families of Zn-dependent metalloproteases

1. MMPs 2. ADAMTS 3. ADAM

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ADAM

A disintegrin and metalloproteinase

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ADAMTS

A disintegrin and metalloproteinase with thrombospondin motif

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EDS type VIIC

Dermatosparaxis: caused by mutation in ADAMTS-2 leading to disorganized collagen fibers which cause skin and connective tissue problems.

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_2-macroglobulin

Endogenous protease inhibitor produced in the liver with bait region containing cleavage sites for many enzymes. When bait region is cleaved conformation changes and traps enzyme which inactivates it.

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Safety considerations with developing enzyme inhibitors as drugs

1. Selectivity 2. Tissue distribution of targeted enzyme 3. Reversible vs irreversible inhibitors

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Irreversible inhibitors

Do not dissociate from enzyme so only way to restore activity is to synthesize more