Biochemistry Test 3

Front 1

Mitochondrial Myopathies

Back 1

abnormaliites in the structure of mitochondria

often detected in skeletal muscle

freq. disrupt mito. repiratory chain, ATP synthase, or ATP/ADP translocator

∴ ↓ ATP synthesis

Front 2

Energy Yield of NADH / FADH2

Back 2

1 NADH --> 3 ATP

1 FADH2 --> 2 ATP

Front 3

Mitochondrial Morphology

Back 3

0.5-1.0 x 2.0-10.0 μm
(size and shape vary by tissue type)

# mito / cell α Energy needs

Front 4

Cristae

Back 4

folds in the inner mito membrane (cause b/c the surface area of the inner membrane is much larger than the outer)

Front 5

Intermembrane Space

Back 5

space between outer mito membrane and inner membrane

environment very similar to cytosol (H+ and other ions can easily cross, as well as small water soluble mol.)

Front 6

Matrix

Back 6

space inside mito inner membrane

*largely impermeable

Front 7

Mito Membrane Contact Sites

Back 7

import sites

Front 8

Fluidity

Back 8

mol. move in plane of membrane at a rate dependent on viscosity of mem. & size of mol. moving

Front 9

Membrane Viscosity

Back 9

*relative proportion of cholesterol and phospholipids

*degree of FA saturation

Front 10

Sidedness

Back 10

transverse mvmt. ("flip-flop") of lipid very slow

Front 11

3 Steps of ATP synthesis

Back 11

1) Respiratory chain
e- --> O2 (final e- acceptor)

2) Establish Proton Gradient
transfer of H+ coupled to e- transf.

3) ATP Synthesis
driven by KE of H+ crossing membrane

Front 12

3 Steps of ATP synthesis
(Protein Complexes)

Back 12

1) respiratory chain (Comp I, II, III, IV)

2) respiratory chain (Comp. I, III, IV)
**NOT II

3) ATP synthase (V)

Front 13

Human mtDNA

Back 13

small, circular, dsDNA
copy # - 2-10
37 genes (13 ox phos, 2 rRNA, 22tRNA), NO introns, overlap

*clear bacterial origin

Front 14

Outer Membrane Architecture

Back 14

50% protein
permeable to small molecules (<10 kDa)
cont. porin channels, Acetyl-CoA synthetase, CPT I, and prot. transporters

Front 15

Inner Membrane Architecture

Back 15

80% protein (& cardiolipin)
complexes I - IV, ATP synthase, transporters, GP dehydrogenase, translocase, and CPT II
CYP450 and UCP proteins

Front 16

Cardiolipin

Back 16

a phospholipid (diphosphatidyl glycerol) only found in mitochondrial inner membrane

enhances lack of permeability to protons

Front 17

Porin

Back 17

a channel forming protein, transmembrane

found in mito. outer membrane
--> cytosol is roughly equal to intermembrane space (via diffusion)

Front 18

Acetyl-CoA synthetase

Back 18

FA metabolism

Front 19

Adenylate Kinase

Back 19

myokinase

in intermembrane space

Front 20

CPT I & CPT II

Back 20

Carnitine acyltransferases I & II

FA metabolism

Front 21

CYP450

Back 21

Cytochrome P-450

STEROIDOGENIC TISSUES ONLY

Front 22

UCP 1

Back 22

Uncoupling protein 1

in brown adipose tissue

can selectively uncouple ox phos / resp. --> energy released as heat to maintain body temp

Front 23

UCP 2 & 3

Back 23

uncoupling proteins

NOT limited to brown adipose tissue

Front 24

Matrix Targeting Sequence

Back 24

'presequence'

matrix & IM proteins transl. in cyto, contain N-term targeting sequence

generally 10-70 aa, rich in basic and hydroxylated aa (lacking acidic) --> folds to α-helix; charged on one side, hydrophobic on other

removed by processing protease in mito. matrix

Front 25

TOMs

Back 25

Translocases of the Outer Membrane

complex with TIMs and other TOMs to bring proteins from cyto into IM or matrix

Front 26

TIMs

Back 26

Translocases of the Inner Membrane

complex with TOMs and other TIMs to bring proteins from cyto into IM or matrix

Front 27

Steps in Mitochondrial Import

Back 27

*many separate TOM/TIM pathways -- share some import prot and do not share others

Unfolded precursor w/ exposed target sequence interacts w/ TOM
(may be held unfolded by chaperone)

Front 28

TOM70

Back 28

binds hydrophobic preproteins destined for inner mito mem. or intermembrane space

Front 29

TOM20

Back 29

binds hydrophillic preproteins destined for matrix

Front 30

TIMs 9, 10, 12 & complex of TIMs 22, 54

Back 30

insertion into inner membrane

Front 31

TIMs 23, 17, 44

Back 31

transport to matrix

assisted by mtHSP70 (uses ATP, req. e- gradient)

Front 32

MPP

Back 32

metal-dependent processing protease

catalyzes removal of presequence in matrix
-->prot. complete processing to mature, fxn form

Front 33

Redox Reactions

Back 33

Oxidation / Reduction

1 or more e- lost by one molecule & gained by another

a.k.a. electron transfer rxn

Front 34

Oxidized

Back 34

lose e-

Front 35

Reduced

Back 35

gain e-

Front 36

OIL RIG

Back 36

Oxidized is loss (lose e-)

Reduced is gain (gain e-)

Front 37

Reductant

Back 37

molecule or atom that reduces another mol.

loses e- and becomes oxidized

Front 38

Oxidant

Back 38

molecule that oxidizes another mol.

gains e- and becomes reduced

Front 39

Redox Potential

Back 39

reflects affinity of mol. for e-

e- flow from reduced mol. of ↓ potential to oxidized molecule of ↑ potential

Front 40

Factors Influencing Direction of Redox Rxn

Back 40

1) relative affinity for e-

2) ratio of concentrations
*alteration allows regulation of redox rxns

Front 41

Standard Reduction Potential

Back 41

Eo'

std. affinity for e-

depends on particular molecule, cannot be altered by cell

Front 42

Actual Reduction Potential

Back 42

E'

observed reduction potentials in vivo
depend on Δ in relative concentrations

Front 43

Functions of FA

Back 43

*Energy Source and Storage

* Membrane Structural Components (PL, SL, and chol.)

*Digestive Aids (bile acids and PL)

*Cofactors and Signalling Molecules

*Protection & Insulation

Front 44

Fat Soluble Vitamins

Back 44

ADEK

Front 45

FA Nomenclature

Back 45

COOH 1

Cα is adjacent to COOH
Cβ comes next, and so on

Cω is the N-terminal C

Front 46

stearic acid

Back 46

18:0

*saturated

Front 47

oleic acid

Back 47

18:1Δ9

Front 48

Myristic Acid

Back 48

14:0

tetradecanoic

Front 49

Pallmitic Acid

Back 49

16:0

hexadecanoic

Front 50

Linoleic Acid

Back 50

18:2Δ9,12

9,12-octadecadienoic

*essential FA

Front 51

α-Linolenic Acid

Back 51

18:3Δ9,12,15

9,12,15-octadecatrienoic

*essential FA

Front 52

gamma-Linolenic Acid

Back 52

18:3Δ6,9,12

6,9,12-octadecatrienoic

Front 53

Arachidonic

Back 53

20:4Δ5,8,11,14

5,8,11,14-eicosatetraenoic

Front 54

EPA

Back 54

20:5Δ5,8,11,14,17

5,8,11,14,17-eicosapentaenoic

Front 55

Amphipathic

Back 55

having one hydrophilic end (carboxyl) and one hypdrophobic end (alkyl chain)

Front 56

FA solubility

Back 56

medium chain (6-12) highly soluble

long chain (>14) less soluble --> form micelles

Front 57

ω number

Back 57

total # of carbons - # of position of last double bond

Front 58

ω-6

Back 58

Linoleic and arachidonic acids

Front 59

ω-3

Back 59

α-linolenic acid and EPA

*best supplied from plant oils and fish oils

Front 60

TAG

Back 60

triacylglycerol

*major form of storage lipid and bulk of dietary lipid

glycerol head group attached to 3 FA backbones via ester linkages

can be simple (one type FA) or mixed (multiple types of FA)

"-ic acid" --> "oyl"

*repel water, ∴ bulk of weight in storage of fuel, not in water + fuel (ex. CHO)

Front 61

emulsification

Back 61

the process of making fat droplets soluble in H2O

i) high body temp liquefies solid fats
ii) peristalsis crushes droplets
iii)ampipathic bile acids (salts) coat droplets, inc. H2O solubility

Front 62

Bile Salts

Back 62

cholesterol derivates

Front 63

Pancreatic Lipase

Back 63

catalyzes hydrolysis of 1 & 3 pos. esters of TAGs

produces 2-monoacyl glycerol (2-MAG) (hydrophillic enough to be brought into cells)

Front 64

Lipolysis

Back 64

hydrolytic cleavage of TAGs

Front 65

esterase

Back 65

hydrolyzes cholesterol esters

Front 66

phospholipase

Back 66

hysdrolyzes membrane phospholipids

Front 67

Absorption of water soluble intermediates

Back 67

gylcerol, short & medium chain FA

enter brush border of intestinal mucosal cells by simple diffusion

(move down concentration gradient)

Front 68

Absorption of low solubility intermediates

Back 68

2-MAG & long chain FA

most stored in micelles. as monomers are abs. via diffusion, more are released from micelles until all are abs.

Front 69

micelles

Back 69

in presence of bile salts, form mixed bilayer, but are stabilized by salts and do not form vesicles

Front 70

Fatty Acyl CoA Synthetase

Back 70

catalyzes activation of FA using ATP and CoA, yields PPi and Acyl CoA

ΔG~0, ∴ driven by breakdown of PPi to 2 Pi

*removes FA from cell (ties up in TAG), thus allowing more FA to enter from lumen of intestine via diffusion

Front 71

Inorganic Pyrophosphatase

Back 71

catalyzes breakdown of PPi --> 2Pi

ΔG = ~ -8

tiead to Fatty acyl CoA synthetase, drives those reactions

Front 72

acyltransferases

Back 72

add acyl groups from Acyl-CoA to 2-MAG

randomly attach activated FA to resynth. TAG

Front 73

steatorrhea

Back 73

excessive lipid in stool

poss from:
-lack of bile (biliary obstruction) causes lack of micelle formation
-pancreatic diseases
-celiac disease (reduces absorptive surface of intestine)

*assoc. w/ deficiencies in fat soluble vitamins and essential FA

Front 74

Rotenone

Back 74

insecticide in tree roots -- paralyzes fish

inihib. comp. I, can't use NADH
*e- flow cont. through II

Front 75

Amytal

Back 75

inhib. compl I

Front 76

Piericidin A

Back 76

inhib. comp. I

Front 77

Antimycin

Back 77

inhib. comp III

Front 78

CO

Back 78

inhib. comp. IV

binds Fe2+ of cyto a3

Front 79

CN & Azide

Back 79

inhib. comp IV

bind Fe3+ form of cyto a3

Front 80

UCP1

Back 80

thermogenin

uncoupler found in brown fat

*resp. doesn't know what ATP synth is doing, still makes e- which still flow back into mito around ATPase

Front 81

LHON

(Leber's Hereditary Optic Neuropathy)

Back 81

loss of central vision (optic nerve death)

usually ♂ in late 20s/early 30s (can affect anyone)

from mtDNA pt. mutations

comp. III also affected

Front 82

KSS

(Kearns-Sayre Syndronme)

Back 82

ocular myopathy

ritinitis pigmentosa and lactic acidosis

single mtDNA deletion (varies in region and size)

*progresses w/ age (due to ↑ proportion of mut DNA over time)

Front 83

MERF

(Myoclonus Epilepsy w/ Ragged Red Fibers)

Back 83

abnormal red muscle fibers in heart, kidney, muscle, and nerve tissues

mut. in tRNA-Lys (* ↓ mito protein synth)
comp. I & IV def.

Front 84

Leigh Syndrome

Back 84

tRNA-Leu tertiary struc. altered by mutation

impedes uridine modification in anticodon, thus less stable

--> general ↓ mito prot. synth.

Front 85

Drug-Induced mtDNA depletions

Back 85

newborns present with only 2-20% norm mtDNA levels

*in AIDS patients on zidovudine: 20-80% norm mtDNA present, can be reversed

Front 86

Reye's Syndrome

Back 86

childhood onset

*acute encephalomyopathy

presents w/ vomiting, coma, hepatomegaly, hypoglycemia

*dangerous changes in liver mito and brain

displacement of pyruvate carboxylase to cyto (poss. b/c of impaired mito import machinery)

*inherited from father (c'est à dire, transloc. to cellular genome)

Front 87

General Treatments of Mitochondrial Disorders

Back 87

co-factor / oxidizable substrate therapies

↓ ROS damage

use substrates for comp. III, IV

myoblast transplantation

delivery of normal mtDNA to mito

*basically, optimize resp. chain rate

Front 88

Stroke Treatment

Back 88

s. caused by occlusion of blood flow into brain (∴↓O2)

use tPA (a clot buster) w/ limited success

*very short therapeutic window!

inhib. GlutR prevents damage (prevents cell from realizing ↓O2, opening holes in IM, losing osmotic pressure, and bursting mito)

Front 89

CsA

(Cyclosporin A

Back 89

immunosuppressive, also approved for transplant rejection

binds Cyp D --> closes pores in mito, reduces risk of ischemia / reperfusion injury

Front 90

binding-change mechanism

Back 90

three beta subunits undergo seq. conf. changes

L-->T-->O

Front 91

DHHP

(dicyclohexylcarbodiimide)

& oligomycin

Back 91

inhibit ATP synthase

Front 92

RCR

(respiratory control ration)

Back 92

indicates how tightly coupled mitochondria are

Front 93

Uncouplers

Back 93

bypass ATP synthase

*causes resp. to go at max. rate (w/out ATP synthesis)

Front 94

Pi/OH- exchanger

ATP/ADP exchanger

Back 94

ATP/ADP exchanged across mito inner membrane

*atractyloside and bongkrekate --| ATP/ADP exch.

Front 95

Homoplasmic shift

Back 95

mutations gradually accumulate in some cells, disappear from others

*due to unequal distribution in segregation when cells divide

Front 96

Subs. Promoting Fat Catabolism

Back 96

F acyl CoA & malonyl CoA --| acetyl CoA carboxylase

Carnitine

Front 97

Subs. Promoting FA and TAG Synth

Back 97

citrate --> acetyl CoA carboxylase

malonyl CoA --| CAT I

Front 98

CHO promotes fat deposition

Back 98

glc. gives cyto Acetyl CoA & NADPH

↑ FAS enzyme

CHO prov. G3P for TAG synth

Front 99

Ketones

Back 99

made, but not used by liver

*liver lacks 30ketoacyl CoA transferase

Front 100

Hormonal Controls of Fat Metabolism

Back 100

Glucagon / Epi: --> cAMP-dependent kinase (PKA)

PKA phosphorylation:
--| acetyl CoA carboxylase
--> hormone sensitive lipase (HSL)

Insulin binds receptor tyrosine kinase, opposes glucagon action

Front 101

Cardiolipin

Back 101

double phospholipid

common in mitochondrial membranes

Front 102

Glycerophospholipids

Back 102

spont. form bilayer vesicles in aqueous solution

formation from PA or DAG

activate head group, SAM as Me donor

Front 103

Phosopholipases

Back 103

cut FA

PLA2s release PUFAs (prostalgandins & thromboxanes for pain; leukotrienes for immune response)

can be potent venoms (snake), chop FA, convert good membrane into a strong detergent, toxic if damage faster than cellular repair

Front 104

Tay Sachs

Back 104

GM2, a ganglioside, accumulation in nervous tissue of children and infants

accum due to defect in Hexosaminidase A

*lysosomal storage disease (absence of a ly. enz. causes problems)

*mental retardation, malformation, death during infancy

Front 105

FH

(Familial Hypercholesterolemia)

Back 105

LDL-R def., inability to take in circulating cholesterol

leads to to oxidative damage, scarring, atherosclerosis

Front 106

CETP

(Cholesterol Ester Transfer Protein)

Back 106

shuttles excess cholesterol from HDL to LDL in exchange for TAGs

Front 107

Serum Albumin

Back 107

has several binding sites for LCFAs

*normal mech. for FA transport in serum

easily saturated mech., cannot carry cholesterol

Front 108

Apo A-I

Back 108

in HDL

structural, LCAT activator

Front 109

Apo B-48

Back 109

in CM

structural, aids LRP binding

Front 110

Apo B-100

Back 110

in VLDL, IDL, LDL

structural, LDL-R interaction

Front 111

Apo C

Back 111

in VLDL, CM, HDL

LPL Activator

Front 112

Apo E

Back 112

in VLDL, IDL, HDL, CM

aids LRP & LDL-R binding

Front 113

apo (a)

Back 113

Lp (a) *modified LDL

unknown fxn, increase risk for CHD

Front 114

LCAT

Back 114

serum protein

activated by Apo As

fxn in CE formation

Front 115

Tangier Disease

Back 115

assoc. w/ HDL deficiency

mut in ABCA1 gene (helps to export excess chol from cells for HDL transport)

presents w/ peripheral neuropathy; mild, no elevated CHD risk

(orange tonsils)

Front 116

Hypobetalipoproteinemia

Back 116

def. of CM, VLDL, LDL

from genetic defects in ApoB

Front 117

Refsum's Disease

Back 117

gen. def. in alpha oxidation

results in buildup of phytanic acids

--> neurological disorder

Front 118

Zellweger Syndrome

Back 118

absence of peroxisomes

LCFA accumulate in tissue

Front 119

Methylmalonic Acidurea

Back 119

buildup of penultimate intermediates in beta-ox (methylmalonate)

from def. in vit. B12

Front 120

Wolman's Syndrome

(Cholesterol Ester Storage Disease)

Back 120

norm LDL uptake

lysosomal esterase def. prevents hydrolysis of CE, thus they accumulate