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KCUMB Biochemistry - Erin > EXAM III Material > Flashcards

EXAM III Material Flashcards

1
Q

Where does the TCA cycle take place?

A

Mitochondrial Matrix

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2
Q

Where is the carbon source from for entry into the TCA cycle?

A

Acetyl CoA via pyruvate

Pyruvate becomes decarboxylated

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3
Q

What is the overview of the TCA cycle?

A

Overall process involves the Oxidation of 2C units producing:

2 CO2 molecules

1 GTP

Electrons via NADH & FADH2

First step is condensation of OAA

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4
Q

What are the enzymes involved in the PDH complex and what are their prosthetic groups?

A

E1 - TPP; catalyzes oxidative decarboxylation of pyruvate

E2 - Lipamide; transfer of acteyl group to CoA –> TCA

E3 - FAD; regeneration of the oxidized form of lipoamide from hihydrolipoamide (2 e- transferred to FAD & NAD+)

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5
Q

What are the catalytic cofactors and stoichiometric cofactors during the TCA rxn of pyruvate to acetyl CoA?

A

Catalytic cofactors:

Thiamine pyrophosphate (TPP)

Lipoic acid

FAD

Stoichiometric cofactors:

CoA

NAD+

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6
Q

What are the 3 steps of acteyl CoA formation from pyruvate?

A

Decarboxylation (E1)

Oxidation

Transfer of actyl group to CoA (E2)

Pyruvate dehydrogenase regeneration (E3)

D.O.T.

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7
Q

What occurs during decarboxylation of pyruvate during the PDH complex?

A

Pyruvate combines with TPP which then becomes decarboxylated to hydroxyethyl-TPP (intermediate) via pyruvate dehydrogenase component E1 using TPP = prosthetic group

Carbanion (TPP) readily attacks carbonyl group of pyruvate causing decarboxylation (H+ on TPP is very acidic)

Product = CO2

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8
Q

What occurs during oxidation in the PDH complex? (E2)

A

Hydroxyethyl group attached to TPP is oxidized to an acteyl group which is then transfered to lipoamide linked to a lysine residue of E1 creating an energy rich thioester bond in acteyllipoamide

(transfer of acteyl group to CoA)

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9
Q

What are characteristics of the pyruvate dehydrogenase complex?

A

Complex containing 60 proteins of E1,E2,E3

LARGE protein

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10
Q

What are the basic features of the mitochondria?

A

Outer membrane; permeable due to VDAC (voltage dep. anion channels

Inner membrane w/ cristae; impermeable = Oxidative Phosphorylation

Intermembrane space

Matrix - TCA & FA oxidation

Semi autonomous - own DNA

Human mito DNA = 16, 569 bp & encodes 13 respiratory chain proteins, rRNAs, tRNAs

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11
Q

What are the electron carriers of oxidative phosphorylation?

A

Coenzyme Q/Ubiquinone

Transfers e- from NADH Q Oxidoreductase & Succinate Q Reductase to Q Cytochrome C Oxidoreductase

Cytochrome C

Shuttles e- from Q Cytochrome C Oxidoreductase to Cyt C Oxidase

Catalyzes reduction of O2

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12
Q

What are the prosthetic groups for Complex I? (plus rxn catalyze)

A

FMN

FeS

NADH + Q + 5Hmatrix –> NAD+ + QH2 + 4H+cytoplasm

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13
Q

What are the prosthetic groups for Complex II?

A

FeS

FAD

No proton pumping, less ATP synthesized from FADH2 oxidation

FADH2 enters via complex II and remains in the complex & transfers its electrons to FeS then Q –> QH2

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14
Q

What are the prosthetic groups for Complex III?

A

Hemes bH, bL, c1

FeS

Passes electrons from QH2 to cyt c transporting 2H+ to cytoplasmic side

QH2 + 2Cyt cox + 2H+matrix –> Q + 2Cyt cred + 4Hcytoplasm

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15
Q

What are the prosthetic groups of Complex IV?

A

CuA

CuB

Heme a

Heme a3

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16
Q

What are the oxidation states of Quinones?

A

Becomes oxidized and reduced:

Q, ubiquinone (oxidized form)

QH2 ubiquinone (reduced form)

Intermediate contains semiquinone radical

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17
Q

What is Friedreich’s Ataxia

A

Mutations in protein Frataxin

Loss of function of small mito protein crucial for FeS cluster synthesis

Affects CNS, PNS, heart, skeletal system = excitable cells

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18
Q

Cytochrome C Oxidase

A

Complex IV

Catalyzes transfer of e- from reduced Cyt c to molecular Oxygen = H2o

Pumps H+ across

Cua is reduced to Cub and Fe in hemea end up binding O2 forming a peroxide bridge which becomes cleaved via 2 more protons releasing water

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19
Q

What are the 2 pathologies that are related to free-radical injury in oxidative phos?

A

Parkinson disease

Ischemia; reperfusion injury

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20
Q

What free radicals form from oxidative phosphorylation and how

A

Due to partial reduction of oxygen

Single electron transfer to O2 = superoxide anion

2e- transfer to O2 = hydrogen peroxide

Both can form hydroxyl radical

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21
Q

What defense mechanism occurs in response to free radicals?

A

Antioxidants;

Superoxide dismutase (SOD)

Catalase

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22
Q

What is the major storage form of lipids?

A

TAGs - triacylglycerols

TG

Glycerol backbone and 3 FA chains

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23
Q

Short and Medium chain FAs in TAGs are digested via what enzymes?

A

Lingual Lipase

Gastric Lipase

<12Cs i.e. TAGs in milk

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24
Q

Define emulsification

A

Suspension into small molecules in the aqueous environment caused by bile salts

Which are released by the gall bladder stimulated by cholecystokinin

Bile salts = amphipathic

Increases SA for absorption

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25
Q

How are bile salts released from the gall bladder?

A

Via Contractions of the gall bladder stimulated by gut hormone cholecystokinin

Bile salts = amphipathic

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26
Q

Which digestive enzyme is the major one that digests FAs? Short, Medium, and Long

A

Pancreatic Lipase

The emulsification of FAs becomes the substrate of pancreatic lipase

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27
Q

What is the role of secretin?

A

Hormone

Released in the stomach in response to acidic material in the stomach causing the release of bicarbonate which increases the pH (6) to establish an optimal environment for intestinal enzymes

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28
Q

What are the 3 steps required to utilize FA as a fuel?

A

Mobilization - TAGs in adipose tissue released & transported

Activation - FA activated and transported into mito.

Degradation - FA breakdown into acetyl-CoA -> TCA cycle

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29
Q

What is the major source of carbone for fatty acid synthesis?

A

Dietary carbohydrates

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30
Q

List characteristics of the mitochondrial genome

A

DNA contains 16, 569 bp and encodes 13 respiratory chain proteins, rRNAs, tRNAs

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31
Q

Which step of the TCA cycle is the only step that directly yields a high energy phosphotransfer compound?

A

Succinyl CoA synthetase

Converts succinyl CoA to Succinate - The cleavage of succinyl-CoA is a high energy bond; which causes the creation of GTP

Yields GTP

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32
Q

Define anaplerotic pathways and explain their significance

A

Metabolic pathways that create intermediates; can be used for other pathways

These are required during low states of energy

OAA can form glucose, alpha-ketoglutarate forms purines and amino acids

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33
Q

During oxidative phosphorylation, where are the protons pumped from the 3 complexes?

A

From the matrix into the inter-membrane space

Protons are returned to the matrix via ATP synthase powering the synthesis of ATP

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34
Q

What are the components of iron sulfur clusters and their importance?

A

Tetrahedrally coordinated to SH groups of 4 Cys residues of protein, 2Fe ions, 2inorganic sulfides and 4 Cys residues

4Fe ions, 2 inorganic sulfides, 4 Cys residues

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35
Q

What is the Chemiosmotic Hypothesis?

A

The pH gradient and membrane potential is generated via ETC with the transport of proteins from matrix to cytoplasmic side of inner membrane.

This constitutes a proton motive force which is used to drive ATP synthesis

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36
Q

What evidence was used for the Chemiosmotic hypothesis?

A

Bacteriorhodopsin in synthetic vesicle

The vesicle was incubated with ADP + Pi and exposed to light and ATP was generated

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37
Q

What are the characeristics of ATP Synthase?

A

Complex V

Embedded in inner membrane

Ball (F1 subunit, protrudes into matrix; proton channel) and Stick (F0 subunit, membrane; proton channel) model

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38
Q

What are the characteristics of the F1 subunit of ATP Synthase?

A

Made up of 5 polypeptide chains with diff. stoichiometries

Alpha3, beta3, gamma, delta, epsilon

Alpha + Beta = hexameric ring, only beta is catalytically active

A stalk above the alpha & beta is made up of gamma and epsilon proteins

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39
Q

What are the 2 ways in which both F0 and F1 subunits are connected to one another in ATP Synthase?

A

Central gamma and epsilon stalk

Exterior column - 1 a su, 2 b su, and delta su

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40
Q

What is the role of the proton gradient in the ETC cycle?

A

Release of the ATP from the synthase

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41
Q

Which protein subunit is the active site of ATP synthase?

A

3 beta su

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42
Q

What are the 3 steps in ATP synthesis?

A
  1. Binding of ADP and Pi (L)
  2. ATP synthesis (T)
  3. Release of ATP (O)

the BAR

Conformations change via gamma su rotation

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43
Q

What are the characteristics of the proton conducting unit of ATP synthase?

A

C subunit made up of 2 alpha helices that span membrane

Contains an Asp in the center of membrane

a subunit has 2 half channels which allows proton to enter and pass partway, but not completely

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44
Q

Define respiratory control

A

Regulation of cellular respiration via ADP levels

Electrons flow thru ETC only when ADP is phosphorylated to ATP

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45
Q

What does Inhibitory factor regulate?

A

ATP synthase; inhibits hydrolytic activity of ATP synthase

Prevents the reverse reaction (ATP breakdown)

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46
Q

Is Inhibitory factor I upregulated or downregulated during ischemia or oxygen deprivation?

A

Upregulated; you do not want ATP synthase pumping due to no oxygen being present as final electron acceptor

IF1 inhibits ATP synthase hydrolytic activity

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47
Q

What is the Warburg effect? (ATP synthase regulation)

A

In cancers where inhibitory factor 1 facilitates the switch from aerobic to anaerobic respiration

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48
Q

Define UCP 1 and explains its usage and mechanism of action, what is it activated by?

A

Uncoupling protein in the IMM = thermogenin

Uncouples oxphos from ATP synthesis where energy is converted to heat rather than ATP

Used to generate heart and maintain body temp.

Brown adipose tissue

rich in mitochondria; reddish brown due to cytochromes & Hb

Activated by fatty acids!!!

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49
Q

Name the 3 proteins that are involved in uncoupling oxphos and ATP synthesis

A

UCP 1

UCP 2

UCP 3

Energy homeostasis

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50
Q

What is the mechanism of action of 2,4-DNP (dinitrophenol) in OxPhos?

A

Uncouples ETC from ATP

Dissipates the proton gradient

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51
Q

What is the antibiotic and antifungal agent used to inhibit influx of protons into ATP synthase? How does it do this?

A

Oligomycin

Binds to c su (F0 = proton channel)

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52
Q

What are the methods of actions of atractyloside and bongkrekic acid on OxPhos?

A

Atractyloside - inhibits ATP export

Bongkrekic acid - inhibits ATP-ADP translocase

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53
Q

Define reperfusion

A

the action of restoring the flow of blood to an organ or tissue, typically after a heart attack or stroke.

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54
Q

What is ATP/energy used for primarily in the brain?

A

Signaling (75%)

Maintaining essential cellular activity (25%)

Metabolic rates higher in gray matter than in white matter

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55
Q

How do energy rich substrates enter the brain for cerebral energy metabolism?

A

Via the blood brain barrier

Transporters in the endothelial cells that uptake glucose and monocarboxylic acids

Cerebral metabolic rate increases during early development and plateaus after maturation

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56
Q

What are the nutrients that the brain utilizes for energy? (4)

A

Glucose - primary

Monocarboxylic acids - lactate

Ketone bodies - acetoacetate and beta hydroxy butyrate (used during suckling due to high fat content of milk)

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57
Q

What is the significance of compartmentalization of metabolism in the brain?

A

During hypoxia, glucose is transported into astrocytes for the formation of lactate that can be utilized by neurons

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58
Q

What metabolic pathways does the brain utilize?

A

Glycolysis

Glycogenolysis

Pentose Phosphate Shunt

Malate Aspartate shuttle

TCA cycle

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59
Q

What are some experimental methods utilized for studying metabolism of the brain?

A

Surgical methods - focal ischemia (middle cerebral artery occlusion); global ischemia (cartid artery occlusion)

In vivi imaging techniques - MRIs, CTs, CAT scans

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60
Q

What experimental method is useful for local rates of glucose and O2 utilization? How does this work?

A

PET Imaging (positron emission tomography)

Uses analogs of glucose (2-deoxy glucose; experimental animals) and 2-fluoro-deoxy glucose (humans)

Rely on quantitative intracellular trapping of DG-6P

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61
Q

How does Magnetic Resonance Spectroscopy (MRS) work?

A

Utilizes glucose labeled with radioactive (3H, 14C, 11C) or stable isotope (13C)

Allows assessment of glucose metabolites as they’re formed in diff. pathways

NMR spectra is obtained

Determines metabolism of precursors via specific neuronal and glial pathways

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62
Q

What are the two types of ischemia?

A

Focal cerebral ischemia - focal disruption of blood flow to a part of the brain (i.e. due to occlusion of an artery by an embolus)

Global cerebral ischemia - transient impairment of blood flow to whole brain (i.e. during cardiac arrest)

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63
Q

List some characteristics of a focal ischemia and what happens, how does it occur, etc.

A

Majority of strokes

Occurs when an artery supplying a brain region is occluded by an embolus, thrombus, or platelet plug

Injury grows over time, necrosis occurs extending to penumbra (area of reversible damage) = surrounds core

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64
Q

Define penumbra

A

During focal ischemia, the rim/area that is surrounding the core

Area of reduced cerebral flow, impaired protein synthesis, preserved energy metabolism

Prompt restoration = thrombolytic agents

During acute phase, want to save the penumbra bc the core is done

Necrosis to penumbra occurs within 3 hours

65
Q

List some characteristics of a global ischemia and what happens, how does it occur, etc.

A

Transient loss of blood flow to entire brain as in cardiac arrest followed by resuscitation

Neurons more sensitive than glial cells

Selective loss of vulnerable neuronal populations i.e. pyramidal cells, purkinje cells, striatal neurons

66
Q

List some problems that occur in terms of biochemistry of ischemia

A

Disruption of blood flow

Reduction/absence of O2 & glucose supply to brain

Impaired energy metabolism

Reduction in ATP levels

Ion pump dysfunction

Disruption of ion gradients

Membrane depolarization

Opening of v.g. channels

Cascade of subsequent signaling events

Cell death in a given brain region

67
Q

What are the events that occur during an ischemic episode in terms of lactate

A

Fall in PO2 = greater lactate production (Paseur effect)

Cells switch to glycolysis = lactic acidosis

K efflux thru K channels

Cellular depolarization/spreading depression propagates in brain tissue

Na+ and Ca2+ gradients collapse

v.g. Ca2+ channels open allowing Ca2+ influx

Release of NT

68
Q

Explain the significance of glutamate in relation to excitotoxic injury

A

Loss of ion gradients leads to build up of ECM glutamate

Glutamate receptor activation = Ca2+ influx = greater ICM Ca2+ = NT release (greater ECM NTs)

Impaired glutamate uptake & excess release

Glutamate receptor activation causes Ca2+ & Zn2+ influx

Activates cytotoxic intracellular pathways

Mito. damage, NOS activation; NO & ROS, lipid free radicals; membrane damage

69
Q

Which ion causes neuronal death in ischemia when accumulated intracellularly? What harmful substances are released? What degrades the cytoskeleton

A

Ca2+

NO and ROS which activate phospholipase A2

Damage to mitochondria, membranes, cytoskeleton = calpain

70
Q

How are ROS formed and what do they do during brain damage

A

Reactive Oxygen Species (H2O2, superoxide, hydroxyl free radicals) are formed when mito. donate electrons to O2 forming reactive unpaired e-

React w/ proteins, lipids, DNA

Structural/functional changes in biomolecules

Cellular dysfunction and eventually cell death

71
Q

What are some major characteristics that occur after microvascular injury and edema in the brain? What are the acute and secondary effects?

A

BBB damaged; greater permeability

Acute = Endothelial cells die

Promotoes leukocyte adhesion causing vessel plugging

Hemorrhagic transformation

Entry of cytokines and pro-inflammatory factors

Edema = further secondary injury

72
Q

What is ischemic apoptosis and what does it cause?

A

Programmed cell death

Deprivation of growth factor support

Oxidative stress

Exposure to inflammatory cytokines

Mito. damage

Induced by factors FAS and TNF-alpha = apoptosis

73
Q

What are some multi-prong approaches for neuroprotective strategies against ischemia of the brain?

A

Thrombolytics

Omega 3 FAs (DHA)

Heat shock resposne

Antioxidants

Growth Factors

GABA agonists

Protein synthesis inhibitors

Caspase inhibitors

74
Q

Define thrombolytics and state what it is used for

A

Thrombolysis/Embolectomy

Breakdown (lysis) of blood clots by pharmacological means, and commonly called clot busting

Infusion of tissue plasminogen activator (TPA)

Reperfusion reestablishes circulation; high risk; may cause fatal edema or intracranial hemorrhage

75
Q

What is the pentose phosphate pathway? What is its purpose?

A

An alternate pathway for glucose oxidation

Begins at G6P via glycolysis

Primary role is to create NADPH and Ribose-5-Phosphate (sugars)

76
Q

What are the products of the pentose phosphate pathway?

A

Ribose-5-phosphate –> pentoses (ribose, deoxyribose)

NADPH (reductive biosynthesis i.e. cholesterol synthesis)

77
Q

What are the two phases of the pentose phosphate pathway?

A

Oxidative Phase I

Non Oxidative Phase

78
Q

What happens during the oxidative phase I of the pentose phosphate pathway?

A

G6P –> Ribulose-5-Phosphate

Defective enzyme causes hemolytic anemia

Forms 2NADPH + CO2

**Rate Limiting

Enzyme = G6P Dehydrogenase

79
Q

What are the fates of the 2NADPH from the first step of the pentose phosphate pathway?

A

Reductive Biosynthesis Reactions:

Cholesterol synthesis

FA synthesis

80
Q

What steps occur during the Non-Oxidative phase of the pentose phosphate pathway?

A

Ribulose-5-Phosphate –> Ribose-5-Phosphate –> Nucleotide Biosynthesis

81
Q

What are the 2 fates of ribose-5-phosphate during the pentose phosphate pathway?

A

Nucleotide Biosynthesis

OR

Fructose-6-Phosphate –> G3P –> Pyruvate

82
Q

What enzyme is involved in the rate limiting step of the pentose phosphate pathway?

A

G6P Dehydrogenase

From G6P –> Ribulose-5-Phosphate

In the Oxidative Phase

83
Q

What occurs when there is a defect in G6P Dehydrogenase of the pentose phosphate pathway?

A

Hemolytic anemia

Causes less NADPH which causes reduced Glutathione in RBCs - Needed for healthy membranes

Glutathione reductase - reduces RBCs membranes

84
Q

What is Mode 1 is the pentose phosphate pathway?

A

R5P > NADPH

F6P, G3P are forming ribose-5-p

85
Q

What occurs in Mode 2 of the pentose phosphate pathway?

A

Balanced

Ribose-5-P = NADPH

Oxidative phase is forming ribose-5-p

86
Q

What occurs in Mode 3 of the pentose phophate pathway?

A

NADPH > Ribose-5-P

Reverse glycolysis to go through oxidative phase

Ribose-5-p switches to glycolysis

87
Q

What occurs during Mode 4 of the pentose phosphate pathway?

A

Both ATP + NADPH is required

Complete glycolysis occurs, ribose-5-p reverses arrows

88
Q

What is the key modulator in maintenance of protein homeostasis? (involved w/ protein folding disorders)

A

Molecular Chaperons

Eliminates misfolded, malfunctional proteins

89
Q

What are the 3 components of the cellular quality control system for protein folding disorders?

A

Proteosomes - eliminates proteins

Autophagy

ERAD - ER-Associated Degradation

90
Q

What is the first known protein-misfolding disease?

Alzheimer’s disease

ALS

Sickle cell anemia

Parkinson’s disease

Cystic fibrosis

A

Sickle cell anemia

91
Q

What are the 5 types of protein-folding related problems?

A

Improper degradation

Improper localization

Dominant-negative mutations

Gain-of-toxic function

Amyloid Accumulation

92
Q

What chaperones are involved in the detection of mutant CTFR and beta-glucosidase? (protein misfolding)

A

HSP90

AHA 1

Inhibition of AHA1 allows for a partially funtional mutant CTFR = therapeutic options

93
Q

What degradation systems can be involved with protein misfolding?

A

Autophagy

ERAD - ER Associated Degradation

Overactivity that can contribute to accumulation of mutant, misfolded, incomplete degraded proteins and can contribute to more severe diseases

94
Q

What is the cause of improper localization during protein diseases?

A

Misfolding of proteins, doesn’t allow them to reach their final destination

Improper subcellular localization

= loss-of-function

gain-of-function

95
Q

What causes AAT deficiency? How can it be treated? Which protein folding disorder is involed?

A

Misfolding of AAT, causing it to stay in the liver where it is synthesized

AAT never gets delivered to the lungs, causing pulmonary emphysema and liver disease

Treatment via enzyme replacement therapy

Causes Loss of Function and Gain of Function

96
Q

What occurs during dominant negative mutations? (protein misfolding) Give an example

A

A mutant protein antagonizes the function of the WT protein

Loss of protein activity, mutant interferes w/ function of WT at cellular and structural levels

Normal conditions, keratin assembles to form intermediate filaments.

With a mutant keratin, interacts w/ WT to form a weak filament that fragments upon mechanical stress = Epidemolysis bullosa (i.e. weak cytoskeleton)

97
Q

What occurs during a gain-of-toxic function in protein misfolding? Describe the 2 examples

A

Protein conformation changes that can cause dominant phenotypes

ApoE in Alzheimer’s Disease - polymorphism in allele (C112R) forms a salt bridge b/w aa that prevents helix for extending. This causes altered lipid binding, mito. dysfunction, inhibition of neurite outgrowth

SRC Kinase in Cancer - mutant v-SRC is active and oncogenic due to loss of autoinhibitory region that’s regulated by phosphorylation by WT

v-SRC is dependent on chaperones (i.e. HSP 90) so if that’s not present, v-SRC is tagged for degradation

98
Q

What occurs during amyloid accumulation of protein misfolding, what are the examples of the problems that it causes? What is the amino acid sequence?

A

Amyloid fibers = insoluble protein

Amyloidogenic proteins = VQIVY sequence (amyloid-related diseases; Alzheimer’s, Parkinsons, cataracts)

Common in elderly, natural aging, if young individuals have ApoE allele from parents, more likely to develop disease w/ mutations early in life

Diseases occur from toxic oligomers (in which amyloid plaques can possibly be a defense mechanism) or membrane-solubilizing pores that distrupts membrane integrity

99
Q

What are some ways in which researchers/pharmaceuticals can remediate protein misfoldings?

A

TTR = Transthyretin protein = amyloidogenic, primary carrier of hormone thyroxine and a retinol transporter

Block aggregate formation

small molecules that act as a stabilizer

site-specific antibodies that recognize conformational changes, sequence specific = VQIVY

Intrinsic induction of stress defence programs & resulting adaptation can increase life expectancy

Caloric restriction (Hormetic stress - adaptive response to stress)

100
Q

Define proteostasis, what steps are required of proteins during this process? What pathways ensure proteostasis in the cytosol, ER, and mito.?

A

The maintenance of protein homeostasis

Protein production, folding, degradation

UPR - unfolding protein response

Cytosol = HSP

ER = UPRER

Mito. = UPRmt

101
Q

What are the ways in which PDH is regulated?

A

Allosterically via Acetyl CoA which directly inhibits E2

Phosphoylation via Phosphatase and Kinase

Pyruvate, Ca2+ (muscle contraction), Insulin (FA synthesis), and ADP activate Phosphatase to make dephosphorylate and make PDH active = low energy states

While Acetyl-CoA, ATP, & NADH activate kinase = high energy states

102
Q

Describe the unique features of alpha-ketoglutarate dehydrogenase and explain why it’s important

A

Complex is similar to pyruvate dehydrogenase

In PDH —> Acetyl-CoA, NADH, CO2

In alpha-keto. —> Succinyl-CoA, NADH, CO2

Both catalyze an alpha-ketoacid and create a thioester linkage with CoA

103
Q

What 3 enzymes/steps are highly regulated in the TCA cycle?

A

Pyruvate —> Acetyl-CoA (irreversible)

Isocitrate dehydrogenase; Isocitrate —> alpha-ketoglutarate

alpha-ketoglutarate dehydrogenase; alpha-ketoglutarate —> Succinyl-CoA

104
Q

Explain the regulation of isocitrate dehydrogenase in the TCA cycle; what are the substrates, products, and inhibitors/stimulators?

A

Isocitrate —> alpha-ketoglutarate

Allosterically Stimulated = ADP (low energy)

Inhibitor = NADH, ATP (high energy)

Integration of this step can involve citrate build up which can go back and stop glycolysis if in high energy states

105
Q

Explain the regulation of alpha-ketoglutarate dehydrogenase in the TCA cycle; what are the substrates, products, and inhibitors/stimulators?

A

alpha-ketoglutarate —> Succinyl-CoA

Allosterically inhibited = Succinyl-CoA, NADH, ATP (high energy)

Integration of this step with other cycles occurs during inhibition with a buildup of alpha-ketoglutarate which can be used for amino acid and purine bases synthesis

106
Q

What is the cause of hemolytic anemia? (pentose phosphate)

A

Reduced levels of NADPH in RBCs

Low NADPH levels inhibit G6P-dehydrogenase = reduced glutathione in RBCs; affects their membrane integrity

107
Q

What is the function of leptin? What does it act on?

A

Signals the hypothalamus that you are full

Released from fat

108
Q

What is a possible link in the mechanism between obesity and leptin?

A

Leptin may use a similar mechanism that insulin uses during leptin signaling and obesity (possible leptin resistance)

Pathway is inhibited by suppressors of cytokine signaling SOCS = inhibit inside of the cell even with insulin bound

109
Q

How is overall energy balance regulated in cells?

A

via AMP-activated protein kinase (AMPK)

receives input from metabolic inputs to determine if PK activity should occur

110
Q

What determines whether AMPK is active or inactive?

A

ATP levels; competition b/w ATP/AMP for binding to AMPK allosteric sites

High = Inactive (does not phosphorylate)

Low ATP levels = Allosterically Activated

Phosphorylates targets controlling cellular energy production and consumption

111
Q

What enzyme is involved in the rate limiting step of the urea cycle? Where is it located?

A

Carbamoyl Phosphate Synthetase CPS

Mitochondria

Orange Colored Cats Always Ask For Awesome Umbrellas

112
Q

What two amino acids transport ammonia (NH3+) in the blood? (via transamination rxns)

A

Alanine

Glutamine

113
Q

What are the digestive hormones involved in lipid metabolism?

A

Secretin = bicarbonate release (duodenum)

CCK = bile release

114
Q

What digestive enzymes are involved in lipid metabolism?

A

Esterase

Lingual lipase - short chain

Gastric lipase - short and medium

Pancreatic lipase - all lengths

Phospholipase A2 - removes FA from phospholipids

115
Q

Explain the importance of apoprotein B48

A

Involved with the packaging of TAG into chylomicrons with cholesterol, proteins, phospholipids to be transported though the blood by crossing the lymph via thoracic duct

inside mucosal cell

116
Q

When does a mature chylomicron form? What are the important Apoproteins?

A

Once HDL includes proteins within lymph and blood

ApoE and ApoC

ApoCII - activates capillary lipoprotein lipase to digest the chylomicron

ApoE - is recognized by receptor on surface of liver cells = endocytosis

117
Q

What sites contain lipoprotein lipase for the digestion of chylomicrons?

A

Adipose Tissue

Muscle cells

Which hydrolyzes TG

118
Q

What are the basic steps of FA mobilization from adipocytes?

A

Activated by glucagon + epinephrine

via G-protein

119
Q

What is the importance of glycerol kinase? What other enzyme is utilized?

A

Only used in the liver!!!

Breakdown of glycerol into pyruvate or glucose

Also uses glycerol-P-dehydrogenase

120
Q

What are the 3 ketone bodies that are formed from acetoacetate? Why do they form?

A

D-3-Hydroxy-butyrate

Acetone

Acetoacetate

When acetyl CoA is not being utilized (due to low levels of OAA) they can convert to ketone bodies = fasting or diabetes

121
Q

What is the purpose of the carnitine shuttle? Why must this occur?

A

Carries long-chain fatty acyl CoAs across mitochondria via carnitine acyltransferase I, translocase, acyltransferase II

FA synthesis occurs in the cytoplasm, beta-oxidation occurs in the mito. matrix

122
Q

What step is required before the carnitine shuttle takes place?

A

FA Activation via Acyl-CoA synthetase so that CoA can be transferred to carnitine

123
Q

What enzymes are involved during unsaturated and odd chain FA degradation? What vitamin is required?

A

Isomerase = odd numbered double bonds = propionyl CoA + Acetyl CoA (which is converted to succinyl CoA 4C) = Requires B12; cobalamin

Reductase = even chain

124
Q

What is the major source of carbon for fatty acid synthesis?

A

Dietary carbohydrates

125
Q

What are eicosanoids?

A

Local hormones which act upon growth, inflammation, infection, immunity via Arachidonic acids

Signaling messenger molecules

126
Q

What organ does FA synthesis primarily occur? Where in the cell? What other organs?

A

Liver

Brain, Kidneys, Adipose tissue

Cytoplasm

127
Q

What are the major steps of FA synthesis?

A

Formation of Acetyl CoA

Conversion of Acetyl CoA to Malongyl CoA

Elongation

Desaturation (introduction of double bonds)

128
Q

What two enzymes are involved in forming acetyl-CoA and OAA from pyruvate? (FA synthesis)

A

PC - pyruvate carboxylase forming OAA

PDH - pyruvate dehydrogenase forming acetyl CoA

Both OAA and Acetyl CoA form Citrate

129
Q

What is the rate limiting step in FA biosynthesis? What is the enzyme? What cofactor is required?

A

Conversion of acetyl CoA to Malonyl CoA

via Acetyl CoA carboxylase (ACC)

Carboxylation, CO2 is added to acetyl CoA

Biotin

130
Q

What are the 3 types of regulation of ACC; acetyl CoA carboxylase?

A

Allosteric Regulation = (+) citrate; (-) LC FAs

Phosphorylation (-)/Dephosphorylation(+) = (+) Insulin, (-) Epinephrine, (-) Glucagon

Induction/Repression = gene expression up-regulated high carb/low fat

down-regulated high fat/low carb

131
Q

What are the two steps that occur during the formation of ammonia? What is the prosthetic group and what are the enzymes?

A

Via transamination and oxidative deamination

1. Aminotransferase

2. Glutamate Dehydrogenase

Ammonia is taken off Asp and transferred to alpha-KG

alpha-KG is deaminated via GLDH and ammonium is released and enters urea cycle

prosthetic group = PLP Pyridoxal Phosphate via B6

132
Q

What are the families of Arachidonate acid? (20C FA)

A

PPTL

Timmy Loves Playing (with) Pussy

Thromboxanes - platelet

Leukotrines

Prostaglandins

Prostacyclins

133
Q

What is the major transport of cholesterol?

A

LDL - low density lipoprotein

Contributes to plaque formation

134
Q

Define ketogenic and glucogenic. What two amino acids are strongly ketogenic?

A

Leucine

Lysine

Ketogenic = amino acids that can be converted to ketone bodies or FAs (acetoacetyl CoA)

Glucogenic = amino acids that can be converted to glucose

135
Q

What is ammonium toxic to?

A

The CNS; neural tissue

136
Q

What two enzymes are involved in eliminating free radicals?

A

Superoxide dismutase

Catalase

Antioxidants

Oxygen radical -> Hydrogen peroxide -> Water

137
Q

What is the role of the proton gradient during ETC?

A

To release ATP from ATP synthase

138
Q

Which amino acid is involved with the ATP synthase channel?

A

Asp

Center of subunit c of the proton channel

139
Q

What is the active site of ATP synthase?

A

3 beta su

140
Q

What is the function of ATP translocase during ETC?

A

Allows ATP to leave the mito matrix and ADP enters mito matrix during the formation of ATP due to it being impermeable to mito. membrane

141
Q

Conjugated bilirubin

vs.

Unconjugated bilirubin

A

Conjugated - soluble/direct - contains diglucoronide

Unconjugated - insoluble, bound to albumin

142
Q

What are the biogenic amines that are derived from amino acids?

HS4T(aday) HSN.S.ET

A

He Shits 4Times/day

He Shits NonStop Eliminating Trauma

Histidine - Histamine

Serine - Sghingosine

Tryptophan - Nicotiamide of NAD+

Tryptophan - Serotonin

Tyrosine - Epinephrine

Tyrosin - Thyroxine

143
Q

What is nitric oxide? Which amino acid is it derived from? What enzyme is involved in the formation of NO and what’s the required cofactor?

A

Short-lived signaling molecule via Arginine

NO synthase

BH4 - tetrahydrobiopterin

144
Q

What are the 4 types of NO?

A

nNOS = neurotransmitter

iNOS = killer compound

eNOS = endothial = vasodilator

145
Q

What is the importance of the glutathione system and what chemical element/antioxidant is involved with it?

A

Cytoprotective mechanism, antioxidant, sulfhydryl buffer

Selenium - protects against tissue damage during inflammation and oxidized lipids & hydrogen peroxides (from free radicals)

146
Q

What is the function of AMPK? Under what conditions is it active/inactive?

A

Cellular energy sensor

Phosphorylates targets controlling cellular energy production and consumption

Active = low ATP (high AMP)

Inactive = high ATP

147
Q

What is the function of SIR2 gene? What human gene is it analogous to? What enzyme is utilized?

A

Deacteylases Lysine making a free Nicotiamide

Changes metabolic activity when you restrict caloric intake therefore increasing your life span

Longevity; SIRT1

Enhanced by NAD+

Inhibited by NADH and Nicotinamide

Enzyme = NAMPT

148
Q

Define Long Term Potentiation (LTP), what induces it? Explain the characteristics of this receptor (learning and memory)

A

High frequency, sustained stimulation/signals

AMPA

Ca2+ channel with Glutamate signals

149
Q

What are the relative percentages of oxygen and glucose utilized by brain cells?

A

Oxygen is utilized more than glucose

Oxygen 50-70%

Glucose 10%

150
Q

What is focal ischemia?

A

Middle cerebral artery occlusion

Certain region of the brain is blocked from receiving blood

151
Q

What is global occlusion?

A

Carotid artery occlusion

Entire brain is blocked from receiving blood

152
Q

What nutrients are used during brain imaging and spectroscopy? (ischemia)

A

Glucose and Oxygen

Cannot detect at cellular level, only detects across various brain structures

153
Q

What reaction does PET imaging detect

Glucose analogs?

A

Hexokinase reaction

2-deoxy glucose (animals)

2-fluoro-deoxy glucose (humans)

154
Q

Define the Pasteur effect (ischemia)

A

When a fall in PO2 leads to enhanced lactate production

155
Q

What is the protective strategy of NR2B during ischemia?

A

Injected intravenously 2 hours after stroke

Protected against brain damage and improved neurological functions

156
Q

What death receptors are involved in the extrinsic pathway of ischemic apoptosis?

A

Outside factors activate:

FAS

TNF-alpha

157
Q

Which ion is involved in the intrinsic pathway and which organelles do they affect? What does mito. release that causes apoptosis?

A

Ca2+

Mito. and ER

Mito. = Cytochrome c - caspase-3 activation via apoptosome complex

ER = ER stress caspase 3,9,12

158
Q

What is DHA and what is their importance?

A

omega 3 FA that protects against apoptosis

KCUMB Biochemistry - Erin (5 decks)

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