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Biochemistry Notes, Exams of Biochemistry

Houston Baptist University (HBU)Biochemistry

biochem notes

Typology: Exams

2015/2016

Uploaded on 11/15/2016

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Inhibitors

• Naturally occurring and synthetic; inhibit activity of E’s

• Used to study struct/fn relationships in E’s and determine E mechanisms

• Many drugs

•many are antibiotic, antiviral, antipsychotic, antidepressant

• Many deadly poisons

• 2 classes:

1. Irreversible

• Irreversibly inhibits activity of E

• Either bind v. tightly to E or covalently attached to some vital AA SC on E

• Once bound/covalently attached, doesn’t dissociate from E

• Examples:

• Diisopropylfluorophosphate (DIFP)

■Reagent react with E with AS Ser

■covalently attach self to OH group of Ser SC

■originally a poison nerve gas

■Acetylcholinesterase

• many nerves use acetylcholine as neurotransmitter to

activate skeletal muscles

• action of acetylcholine terminated by ester bond in

Acetylcholinesterase (hydrolase hydrolyze ester bond in

acetylcholine to form choline and acetate)

• DIFP present modifies Ser in AS of Acetylcholinesterase

E inactivated/action of acetylcholine at neuromuscular

junction can’t be terminated

• continued action of acetylcholine sustained muscular

contraction/suffocation because intercostal muscles and

diaphragm can’t relax to allow for expiration of air

• many proteases (E that hydrolyze peptide bonds in

proteins) contain Ser in AS and DIFP inhibits those E

• Aspirin

■pain reliever and anti-inflammatory drug

■acetylsalicylic acid

■eicosanoids

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Inhibitors

Naturally occurring and synthetic; inhibit activity of E’s
Used to study struct/fn relationships in E’s and determine E mechanisms
Many drugs
- (^) many are antibiotic, antiviral, antipsychotic, antidepressant
Many deadly poisons
2 classes:
1. Irreversible
  - Irreversibly inhibits activity of E
  - Either bind v. tightly to E or covalently attached to some vital AA SC on E
  - Once bound/covalently attached, doesn’t dissociate from E
  - Examples:
    - Diisopropylfluorophosphate (DIFP)

■ Reagent react with E with AS Ser ■ (^) covalently attach self to OH group of Ser SC ■ originally a poison nerve gas ■ Acetylcholinesterase

many nerves use acetylcholine as neurotransmitter to activate skeletal muscles
action of acetylcholine terminated by ester bond in Acetylcholinesterase (hydrolase hydrolyze ester bond in acetylcholine to form choline and acetate)
DIFP present modifies Ser in AS of Acetylcholinesterase E inactivated/action of acetylcholine at neuromuscular junction can’t be terminated
continued action of acetylcholine sustained muscular contraction/suffocation because intercostal muscles and diaphragm can’t relax to allow for expiration of air
many proteases (E that hydrolyze peptide bonds in proteins) contain Ser in AS and DIFP inhibits those E
Aspirin ■ pain reliever and anti-inflammatory drug ■ (^) acetylsalicylic acid ■ eicosanoids

modulate pain and inflammation
synthesized from arachidonate by series of E catalyzed rxns ■ Cyclooxygenase
1st^ E of synthesis pathway
required for synthesis of Eicosanoids ■ Irreversible inhibits against Cox
acetate group transferred from salicylic acid to hydroxyl group of Ser SC in AS of E
E inactivated
Eicosanoids not synthesized
Pain and inflammation reduced

(^) Reversible

Reversibly inhibit activity of E
Use H bonds, hydrophobic interactions, and/or salt bridges to bind weakly to E and remain attached to E for brief period of time; then dissociate from E
cycle repeats as long as I present in solution with E
establish equilibrium between bound form and unbound form (inhibitor free in solution)
E inhibited when I bound
activity restored when I dissociates from E when I falls off and reenters solution
2 Types:

(^) Competitive

Look like S with respect to size, shape, and surface changes
Bind to E at AS by same weak interactions used by normal S
E cannot convert I to P
When I bound S cannot bind because BS occupied by I
Effect overcome by increasing [S]
As [S} increases, chances of E encountering S before encountering I increases
At very high [S], E very seldom, if ever, bound to I molecule
High [S] overcome action of I, high [S] can outcompete I for binding to S site
Increase in Km
Vmax unchanged

Noncompetitive

Don’t look like S and don’t bind at S BS
Bind to site on E away from AS
Binding prevents E from undergoing conformational changes necessary for induced fit
if E cannot undergo those changes, cannot catalyze rxn
action cannot be overcome by more [S] because I doesn’t bind at S BS
Vmax decreased
Km unchanged

Competitive

bind only to ES complex but not to free E
parallel lines for LWB

Mixed

E of homeostasis & blood coagulation also synthesized as zymogens and activated by proteases at injury site

Reversible Covalent Modification

small chem group added to or removed from E
(^) addition or removal of small group increases or decreases activity of E
small group usually phosphate group
when group added, either increase or decrease activity
protein kinases are class of E that add phosphate to other proteins or E
transfer phosphate from ATP to protein to form ADP and phosphorylated protein
Protein phosphatases
remove phosphate
S are phosphoprotein and water
hydrolyze phosphoester bond to form dephosphorylated protein
(^) reversible covalent modification is fast; E activity controlled within seconds
Example: ■ E needs to be turned on ■ cell does by adding phosphate to E ■ increased E activity accomplishes some cellular task ■ activity no longer needed cell removes phosphate ■ activity turned off

Feedback Inhibition

P of E acts as competitive I against E that formed it
Feedback inhibition prevents over production of particular P
(^) very rapid
fraction of second to see effects within cell

Allosteric Control

All have quaternary structure
All allosteric E composed of 2 or more subunits
Each subunit has at least 2 BS
1 BS for S
site binds S and orients so AS can perform catalytic function of E
2 nd^ BS is Allosteric site
Site that binds small molecules called allosteric effectors ■ Positive allosteric effectors
when bound to allosteric site, increase E activity ■ Negative allosteric effectors
when bound to allosteric site, decrease E activity

allosteric E don’t follow MM kinetics
- plot of Vo vs [S] for nonallosteric E is rectangular hyperbola
- plot Vo vs [S] for allosteric E is sigmoidal shape ■ at low [S], E has little activity because low affinity for S ■ (^) at certain [S], activity of E increases dramatically - E switch from less active to more active form - increase in affinity of E for S and change to 3D folded structure of protein ■ function changes same (less to more and 3D) ■ T state - tense conformation - less active/inactive, low affinity ■ R state - relaxed conformation - (^) more active/high affinity ■ equilibrium between T state and R state ■ as [S] increases, equilibrium shifts toward R state
Allosteric effectors
- change point at which E switch from less active to more active form
- Positive Allosteric Effectors ■ decrease [S] required to switch E from less active to more active conformation ■ make it easier for E to switch from T state to R state ■ switch T >R equilibrium toward R state
- (^) Negative Allosteric Effectors ■ increase [S] required to switch E from less active to more active conformation ■ make it more difficult for E to switch from T state to R state ■ switch T >R equilibrium toward T state
- Example ■ Hemoglobin (Hb) - allosteric effector - binds O2 in lungs and transports it to tissues

■ Hb cooperativity

deoxygenated Hb
- 8 additional salt bridges (ionic interactions) not found in oxy ■ (^) 6 of 8 between chains of Hb - subunits bind tightly to each other and stabilize each other
- oxygenating on subunit, Fe+2 binds and O2 and Fe +2 fits back into plane of heme ■ Fe+2 no longer puckered out ■ movement pulls His SC which is liganded to Fe+2 toward heme ring, inducing conformational change in protein and breaking subunit interactions found in deoxy ■ (^) most CO2 carried to lungs in form of bicarbonate ion

■ Proximal vs distal

In Mb and Hb:

heme is covalently linked with his F8(8th residue of F helix) closer to heme iron proximal histidine (closer histidine)
other key his responsible for stabilization of O2 in E7 (7th residue of E helix) is far from heme iron distal.
6th^ act as gate (either His or O2)

■ 2 Negative allosteric effectors of Hb

H+ (hydrogen ion)
- generated in tissue as byproduct of metabolism ■ CO2 generated as waste
- (^) CO2 enter blood, then enter RBC where react with H2O to form H2CO3 (carbonic acid)
- RBC contain E carbonic anhydrase that catalyze: CO2 +H2O > H2CO
- carbonic acid is WA that rapidly ionize to H+ and HCO3- ■ H+ liberated acts as negative allosteric effector for HB
- PH 7.2 Hb decreased affinity for O
2,3-bisphosphoglycerate (BPG)
- (^) As Hb releases O2 in tissues, BPG binds to Hb ■ decreases its affinity for oxygen ■ makes easier for O2 to unbind from Hb
- Hb normally: ■ when RBC enter lungs, deoxygenated - Hb has little O2 bound, BPG bound to Hb, pH within RBC is 7.1-7. - air in lungs rich in O2 and poor in CO - low level if CO2 in lungs shifts equilibrium of carbonic anhydrase reaction toward CO

higher pH
Hb binds O
Hb releases H+
actively metabolizing muscle
(^) lower pH because production of H+
Hb releases O
Hb binds H+
gets more o2 than resting muscles ■ Myoglobin
not allosterically effected
single polypeptide chain 153 AA
single heme group in hydrophobic pocket
8 regions of alpha helix/no regions beta sheet
most polar SC on surface
(^) nonpolar SC folded to interior
2 His SC in interior, involved with interaction with heme group
Fe(II) of heme has 6 coordination sites
4 interact with N atoms of Heme
1 with N of His SC
1 with either: ■ O ■ N of 2nd^ His SC Myoglobin Hemoglobin

Function: Warehouse (Storage) Function: Delivery Truck (Transport)

O2 storage in muscles O2 transport monomer tetramer (a2b2) binds O2 at low pressures must bind O2 strongly and release easily 50% saturation at 1 Torr lungs: 100% O2 saturation at high pressures (100 Torr) hyperbolic loading curve capillaries of active muscles: <50% saturation at low pressures (20 Torr) sigmoidal loading curve

group of lipids hydrolyzed/broken down into precursors by hot base are called saponifiable lipids
soaps form water insoluble salts when used in water containing Ca(II), Mg(II), and Fe(II) (hard water)
(^) reactions with acids/bases as catalysts
saponification
Saponifiable lipids
Fatty acids
largest group produced by saponification
LC monocarboxylic acids
saturated
only C-C
unsaturated
at least 1 C=C
(^) lower mp than saturated
greater the degree of unsaturation, lower the melting point
11 common FA comprise about 90% FA in cells
all contain even number C’s
pH 7.4, ionized

donated ionizable H+ on CA group to water, forming negative carboxylate ion
charged forms named with ate suffix
db in unsaturated are all cis
(^) linoleate and linolenate essential for normal growth and development but obtained from diet
sodium salts are soaps
omega-3 FA
polyunsaturated
contain more than 1 db
1st^ db counting from methyl end located at 3 rd^ C
(^) alpha-linolenic acid
humans synthesize other omega-3’s from ALA
eicosapentaenoic acid (EPA) 20:5n-
docosahexanoic acid (DHA) 22:6n-
usually marine derived
ALA plant derived
Glycerol
2 nd^ most abundant of saponification mix
3 C trialcohol
skin softener and laxative
Polar alcohols
ethanolamine
polar ROH
primary amine group
charged at pH 7.
amino group accepts ammonium ion
*only ionized in cell
(^) choline
polar ROH
positively charged quaternary ammonium ion group
charged at pH 7.
amino group accepts ammonium ion
*only ionized in cell
serine
polar ROH
primary amine group
CA group
(^) actually an AA
charged at pH 7.
amino group accepts ammonium ion
CA on serine ionize

polyunsaturated fat
- 2 or more unsaturated FA
- liquids at RT
as length of FA increases, melting point increases
(^) as number of C=C increases, melting point decreases
hydrogenation
- conversion of polyunsaturated fats to monounsaturated and saturated fats
- alkanes hydrogenated in addition reaction
  - H added across db to form sb
  - same rxn
- hydrogenation performed, liquid polyunsaturated converted to semi- solid mono or solid saturated - margarine is example
TG
- (^) ester of glycerol with 3 FA
phosphoglycerides
glycerol molecule with phosphate ion
2 FA in ester linkage to C 2 and 3 of glycerol
phosphate group in ester linkage to hydroxyl on C 1 of glycerol
phosphatidate (phosphatidic acid) is simplest PG
1 ROH group of glycerol esterified by phosphoric acid rather than CA phosphatidic acid produced
cell contain very little phosphatidate
precursor of synthesis of other PG
(^) cell converts it to PG by adding 1 of polar ROH to phosphate group
ester linkage formed between OH on polar ROH and phosphate group
4 major
phosphatidylcholine
choline linked to phosphatidate
lecithin
phosphatidylethanolamine
ethanolamine linked to phosphatidate
phosphatidylserine
serine linked to phosphatidate
(^) phosphatidylinositol
inositol linked to phosphatidate
components of cell membrane
cell membrane composed of lipid and protein along with some carbs if eukaryotic
not used for energy storage
part of structure that keep outside out and inside in
PG have unique structural function that allow to perform task as components of cell membranes
polar head
(^) nonpolar tail
Sphingolipids
don’t contain glycerol
backbone is Sphingosine

discovered by Thudichum name after sphinx
contain Sphingosine, LC amino ROH
found in plants and animals
abundant nervous system
(^) structurally similar to phospholipids
Ceramides
- simplest of sphingolipids
- molecule of Sphingosine to which FA covalently linked
  - amide bond between carboxyl of FA and amino N on C2 of Sphingosine
- cell contain very little (most used as precursor for other sphingolipids)
- small amount in cell is part of lipids that make up cell membrane
sphingomyelin
- phosphate covalently linked to hydroxyl on C1 of Sphingosine by ester bond
- either choline or ethanolamine covalently linked to phosphate by 2nd ester bond
- FA in amide linkage to N on C
- amphipathic
- 1 st^ isolated from myelin of brain and spinal cord
  - rich in nervous tissue
  - present in cell membrane
cerebrosides
FA in amide linkage on C
single monosaccharide (glucose or galactose) in glycosidic linkage to hydroxyl on C1 of Sphingosine
FA in amide linkage to N on C
amphipathic
1 st^ isolated from cerebrum of brain
also in cell membranes
gangliosides
heteropolysaccharide of 3-15 sugar residues attached to C1 of ceramide by glycosidic bond
heteropolysaccharide can contain glucose, galactose, mannose, N- acetylgalactoseamine, and/or sialic acid
(^) amphipathic
1 st^ isolated from ganglia of brain and spinal cord
the 3 heteropolysaccharides that determine whether individual has type A, B, or O blood are examples of heteropolysaccharides that are attached to Sphingosine to form ganglioside
Nonsaponifiable lipids
cannot be hydrolyzed into smaller molecules
(^) do not contain ester or amide bond
individual nonpolar hydrophobic molecules
3 major classes
eicosanoids
fat soluble vitamins
A, D, E, K

can move from one end of cell to other in few seconds
lipids rarely move between layers
- lipid in outer layer rarely flip flops into the inner layer and vice versa
cell membranes must be fluid to do function
life forms found over wide range of temps, membranes must be fluid over wide range of temps
typical phospholipid takes 10^9 times greater to flip-flop across a membrane than to diffuse a distance of just 50 A in lateral direction
controlled by 2 factors
controlled by ratio of saturated to unsaturated FA in membrane lipids
(^) increasing amount of saturated FA decreases the fluidity
increasing [unsaturated FA] increases fluidity
cis db in unsaturated puts kink in molecule
kinky unsaturated FA don’t allow lipids to pack together
bacteria and animals from cold climates have membrane lipids (PG and sphingolipids) with high proportion of unsaturated FA
kinky FA have low melting points membranes remain fluid
kink causes disorder in packing against other chains
disorder causes greater fluidity in membranes with cis db vs saturated FA chains
bacteria and animals that live in hot climates have membrane lipids with high proportion of saturated FA
straight FA have high melting points
(^) controlled by amount of cholesterol dissolved in membrane
presence of cholesterol reduces fluidity by stabilizing extended chain conformations of hydrocarbon tails of FA via hydrocarbon interactions
sidedness
cell membrane, plasma membrane has definite sidedness/orientation
outside layer of lipid bilayer, layer in contact with extracellular water (OUTER LEAFLET) can be distinguished from the inside layer
layer in contact with intracellular water (INNER LEAFLET)
(^) Each leaflet has characteristic phospholipid composition
cerebrosides, gangliosides, sphingomyelins only in outer leaflet
sugar attached to cerebrosides and heteropolysaccharide attached to gangliosides orient molecules correctly in membrane

polysaccharide directed extracellularly, toward outside of cell
2 types of proteins associated with cell membrane
extrinsic/peripheral
membrane proteins bound to and interact with only 1 surface of membrane
bind to and interact with polar heads of membrane lipids by H bond and/or dipole-dipole (electrostatic) interactions
also bind to surfaces of intergral membrane proteins
glycoproteins
extrinsic proteins associated with outer leaflet and many intrinsic proteins
heteropolysaccharides signal to cell that these proteins are to be embedded in cell membrane and they orient protein correctly in membrane
(^) heteropolysaccharide always on exterior of cell (pointing out) where it can interact/H bond with extracellular water
embedded and interact with membrane lipids move along cell surface as membrane lipids move constant motion mosaic of lipids and proteins fluid mosaic model of membranes
intrinsic/integral/transmembrane proteins
embedded within molecule and extend through it
parts of protein exposed both inside and outside of cell
parts that interact with polar surfaces of membrane interact by H bond and/or dipole-dipole (electrostatic) interactions
parts that interact with nonpolar regions do so by hydrophobic interactions
examples:
molecular transporters and hormone receptors (promote 2D diffusion vs 3D diffusion)
antigenic determinants and cell-cell contact molecules

Biochemistry Notes, Exams of Biochemistry

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