Test 5 Biochemistry

Front 1

PPARγ

Back 1

transcription factor
it activates transcription of adiponectin which increases [AMP], which activates AMP KINASE

Front 2

Adiponectin

Back 2

adipose tissue specific hormone

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AMPKinase

Back 3

an [AMP]-dependent kinase
Increases fatty acid uptake and catabolism
Increases muscle glucose uptake
Inhibits energy consuming processes and activates energy producting processes
Phosphorylates AcCoA carboxylase and decreases production of malonylCoA
Inhibirion of carnitine acyltransferase is lifted
FAs are transferred to mitochondrial matrix and FA oxidation increases

Front 4

Thiazolidinediones

Back 4

increase levels of adiponectin by enhancing transcription of its gene via PPARγ activation
Adiponectin indirectly activates AMPkinase

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Exercise and Insulin-independent Glucose transport in skeletal muscle

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Exercise activares amp-kinase as AMP/ATP ratio increases
AMP-kinases activate translocation of GLUT4 transporter to membrane
Muscle increases uptake of glucose from bloodstream
High level contraction also increase intracellular [Ca++] and calmodulin kinase activity which may also be involved in this process
Phenomenon extremely important for diabetic blood glucose management

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Diabetic therapies

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Diet and exercise
Glucose monitoring
Oral anti-diabetics
Insulin therapies

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Hypoglycemia

Back 7

Symptoms:
Confusion
irritability
sweating
shakiness
unconsciousness
Rule of 15:
If blood glucose <70 mg% then 15g carbohydrates will inc. blood glucose by 15mg% in 15 min.

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Brain needs Glucose

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Normal: ~4 mM
MW = 180
.004 x 180 = .72 g/L
or 720 mg/L
or 72 mg/dL
or 72 mg%
Renal threshold = 180-200mg%

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Long term diabetes

Back 9

increased risk for:
Cardiovascular disease and stroke
end stage renal disease
peripheral neuropathy
diabetic retinopathy
prolonged wound healing
infection

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AGEs

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Advanced Glycation End Products:
Some proteins are more profoundly affected by AGE formation than others. For example colagen is thought to cross link excessibely following glyceration which leads to thickening of the basal lamina of blood vessels

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RAGE

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Receptors of Advanced Glycation End Products:
-Receptors for a clase of ligands, NOT a specific ligand
-Ligand-receptors binding triggers response that increases oxidative stress and mimics chronic inflammation via an important inflammatory regulator - NFκB
-RAGE Activation also induces synthesis of more RAGE
-Soluble RAGE (sRAGE) intercepts ligands before they bind to signal transducig full-length RAGE
-Blocks negative effects of AGE on vasculature

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Polyol Pathway

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Some tisse sends excess glucose through this pathway, leading to some of the major complications of diabetes such as retinopathy, neuropathy, and vascular changes

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Increased ROS

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Increase ROS from excess glucose leads to chronic 'pseudo-inflammation'

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Important signaling mechanisms

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-Blood pressure regulation by regulatory hormose that activate PKC and PKG
-Inflammation from NFκB and Glucocorticoids
-Growth and Differeentiation with vitamins A & D, oxygen sensing, integrins
-Neurotransmission with ligand and voltage gated ion channels

Front 15

Blood Pressure Regulation

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-PKC activation is usually initiated by serpentine receptors assiciated with Gq proteins
-PKG activation is via guanylate cyclase receptor enzymes

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2 ways to alter blood pressure

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ALTER BLOOD VOLUME
-Vasopressin (ADH): from posterior pituitary
-Aldosterone from adrenal cortex
ALTER VESSEL DIAMETER (CONSTRICTION/DIALATION)
-Renin: from kidney
-Angiotensin: from circulation
-Atrial Natriuretic Factor (ANF): from heart
-Nitric Oxide: from all over the place

Front 17

Vasopressin

Back 17

THE WATER MONITOR
-↓ blood pressure or ↑ in [Na+] signals hypothalamus/posterior pituitary secretion of ADH
- Serpentine ADH receptors on distal tubules of kidnes activate Gs, adenylate cyclase, cAMP, PKA
-PKA activation results in insertion of aquaporins in distal tubule cell membrane so H2O is reabsorbed

Front 18

PKA

Back 18

when activated results in insertion of aquaporins in distal tubule cell membrane, causing H2O to reabsorb

Front 19

ADH

Back 19

Vasopressin, released from posterior pituitary

Front 20

Hormome BP regulators

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Vasopressin (ADH)
Aldosterone

Front 21

Activation mechanism of PKA

Back 21

Serpentine receptors in kidney activate Gs, adenylate cyclase, cAMP, PKA

Front 22

Aldosterone

Back 22

steroid hormone from adrenal cortex in response to LOW [Na+]
Causes kidney to import Na+ back into bloodstream
Water follows salt

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Vasoconstrictors/Vasodialators

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Renin --> Angiotensinogen--> Angiotensin I --> Antiotensin II

Front 24

Angiotensin II

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Potent vasoconstrictor
Causes bolood volume increase by stimulating adrenals to release aldosterone and pituitary to release ADH

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Gq

Back 25

Protein activated by hormone receptor in Angiotensin II

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PLC

Back 26

Phospholipase C, activated by Gq in Angiotensin II mechanism

Front 27

Phosphatidylinositol-4,5-bisphosphate

Back 27

Membrane phospholipid that is hydrolized by PLC and releases DAG

Front 28

DAG

Back 28

Diacylglycerol (DAG) activates PKC

Front 29

IP3

Back 29

-released by phosphatidylinositol-4,5-bisphosphate and opens Ca++ channels
-Water soluble and diffueses out of the plasma membrane to activate receptors in the ER

Front 30

Phorbol Esters (TPA)

Back 30

-chemical signal disruptor
-activate PKC by mimicking DAG
-Very stable, so effect last much longer than DAG

Front 31

A231887

Back 31

Chemical signal disruptor that is Ca++ ionophore

Front 32

Okadaic Acid

Back 32

Tumor promoter
Phosphatase inihibitor

Front 33

PKC

Back 33

-Phosphorylates Ser/Thr residues of target proteins
-Also activated by Ca++
-Sever isozymes have been identified with characteristic tissue specificity and sensitivites to modulators

Front 34

Ca++

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cytosolic [Ca++] can increase 100 fold very quickly
activates many proteins, including PKC

Front 35

Hormones mediated by Phospholipase C/IP3-mediated Hormones

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acetylcholine
glutamate
oxytocin/vasopressin
thyrotropin releasing hormone
gonadotropin releasing hormone
thromboxane A2

Front 36

Calmodulin

Back 36

-protein with 4 Ca++ binding sites
-modulates many proteins including cyclic nucleotide phosphodiesterase

Front 37

Cyclic Nucleotide Phosphodiesterase

Back 37

breaks down cAMP

Front 38

Ca++/Calmodulin dependent protein kinase targets

Back 38

-cAMP specific phosphodiesterase
-NO synthase
-PI-3 Kinase
-Myosin light chain kinase (MLCK)

Front 39

Cholera Toxin

Back 39

-Interfere with G proteins
-Made permanently active by ADP-ribosylate Gsα
-Results in high cAMP in intestinal epithelium causing secretion of Cl-, HCO3 and H2O into intestinal lumen

Front 40

Pertussis Toxin

Back 40

-ADP-ribosylates Gi so adenylate cyclase is not inhibited
-cAMP increases in lung epithelium causing increased muccous secretion

Front 41

Guanylate Cyclase

Back 41

-simplier to but similar to cAMP signaling
-No G protein
-activates cGMP-dependent protein kinase (PKG)
-interstinal epitnelium, heart, blood, brain, kidney collecting tubules
-Important for BP regulation

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Integral member proteins of Guanylate Cyclase

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Activated by atrial natriuretic factor ANF

Front 43

Cytosolic protein w/ associated heme Guanylate Cyclase

Back 43

Activated by nitric acid (NO)

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ANF

Back 44

-binds type 1 GC receptor --> Increases cGMP levels --> activates PKG
-in kidney, PKG targets Na+ channels of collecting tubules to enhance excretion of Na+, water follows

Front 45

Nitric Oxide

Back 45

-first gas recognized as biological messenger
-free radical
-basis of nitroglycerin's action

Front 46

Nitroglycerin

Back 46

-slowly degrades to NO
-NO binds guanylate cyclease and increases cGMP levels
-PKG activation occurs and Ca++ relaxes heart

Front 47

cGMP Phosphodiesterase

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breaks down cGMP
subtypes of enzyme are inhibited by viagra--extending localized vasodilation

Front 48

PKG

Back 48

-regulatory domain binds with cGMP
-phosphorlates Ser/Thr

Front 49

Match Activator and Signaling Mechanism:
Activator--
1. Bacterial products
2. Cytokines
3. Nitric Oxide
4. Eicosinoids

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A. Toll receptor/NFκB
B. JAK/STAT
C. Guanylate cyclase/PKG
D. Serpentine/PKC

Front 50

Toll Receptors

Back 50

activated by PAMPs or flagella proteins
activate tow major porinflammatory transcription factors AP-1 and NFκB

Front 51

PAMPs

Back 51

Pathogen associated molecular patterns, like lipopolysaccharide
Activators of Toll receptors

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NFκB

Back 52

-transcription factor
-maintained in cytoplasm bound by inhibitor IκB
-Activates gene expression for many inflammatory cytokines and synthetic enzymes for inflamatory mediators
-Possible role in cancer

Front 53

IκB

Back 53

-Inhibitor for NFκB
-Phosphorylation target for many kinases
-Once phosphorylated, it degrades and releases NFκB so that it can enter nucleus

Front 54

JAK/STAT

Back 54

-Signaling of many cytokines
-many interleukins and leptin use this pathway
-Janus Kinase
-Signal Transducing Activators of Transcription

Front 55

Steroid Hormones

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-Lipophillic, so they primarily us intracellular receptors that are transcription factores
-Glucocorticoids are steroid hormones

Front 56

Glucocorticoid

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-Signals glucocorticoid receptor (GR) in cytoplasm
-Glucocorticoid acts as transcription factor and switches "off" inflammation
-NFκB and AP1 is repressed by GR
-STAT is enhanced by GR

Front 57

Hsp90

Back 57

maintains Clucocorticoid receptor in the cytoplasm

Front 58

Growth Factors

Back 58

-Required for wound healing
-most recognize receptor tyrosine kinases
-Most growth factors activate MAP
-receptor of tyrosine kinase leases to activation of a kinase cascated that ultimately activates genes for cell division

Front 59

Milti-kinase cascades activated by growth factors

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PI-3 Kinase
Akt
Mitogen activated kinases, etc

Front 60

Retinoic Acid

Back 60

-Vit. A
-INCREASES:
-Disabled 2 --> blocks MARK
-p21, p27 --> cdk inhibitors
-DECREASES:
-Talomerase --> induces senescence
-Cyclin D3 --> inhibits proliferation

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Vit. D Signaling

Back 61

-Regulates genes needed for Ca++ megabolism, bone growth, and remodeling, cell differentiation, etc.
- Other VDR modulator proteins: calrectulin, SUG

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TGFβ/BMP

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what does it regulate?

Front 63

Hypoxia

Back 63

signals angiogenesis via HIF-1

Front 64

Integrin

Back 64

enteract with ECM proteins

Front 65

Neurotransmission

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Lignad and voltage-gated ion channels

Front 66

Gated ion channels

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Nicotinic Acetylcholine receptors
Describe mechanism

Front 67

Voltage Gated Channels

Back 67

-voltage gated Na+ channels are closed in polarized state
-open in response to change of charge in membrane potential

Front 68

3 steps of Nerve impulse

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1. initiation: ligand-gated ion channel
2. Propagation: voltage ion channels
3. termination: voltage-gated Ca++channel

Front 69

Tubocurarine

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-toxin of curare, cobratoxin, and bungarotoxin
-blocks the acetylcholine receptor

Front 70

Tetrodotoxin

Back 70

-found in puffer fish
-blocks Na+ channels along axons and halt nerve impulses

Front 71

Taste signaling

Back 71

-Use sweet receptors (SR)
-Signal Gdust to activate adenyl cyclase

Front 72

Functions of Nucleotides

Back 72

-Storage and flow of genetic information, DNA and RNA
-Storage and source of energy, ATP and GTP bonds
- Component of key co-factors: NAD, FAD, co-A and SAM
-Form activated intermediates: UDP in clucose/glycogen and CDP-diacylglycerol in phospholipid synthesis
-Metabolic regulators: CAMP cGMP are cellular messengers

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3 Components of Nucleotides

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Nitrogenous Base
Pentose Sugar
1+ Phosphate group

Front 74

Nitrogenous Bases:
How many rings?

Back 74

Purine-2 ring structure
Pyrimidine- 1 ring structure

Front 75

Describe the substituents of the Pyrimidines

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Uracil
Thymine
Cytosine

Front 76

Describe the substituents of the Purines

Back 76

Adenine
Guanine

Front 77

What is a nucleoside?

Back 77

C1 attachment of a nitrogenous base to a sugar

Front 78

What is a nucleotide

Back 78

-attachment of a phosphate to the sugar component of the nucleoside.
-Phosphates are NEVER attached to the base

Front 79

Describe naming systems for nucleosides

Back 79

Purines:
-Replace -ine with OSINE
-use deoxy not ribo
Pyrimidines
-Add -idine: cytidine, thymidine, uridine
-use deoxy and omit ribo

Front 80

Describe naming for nucleotides

Back 80

2 systems:
Add phosphates after nucleoside and use ' prime for sugar carbon:
-adenosine 3'-monophosphate
-deoxythymidine 5'-diphosphate
-5' can be abbreviated to dTDP
For 5' monophosphates
-add -ylate: adenylate, guanylate, cytidylate

Front 81

Overview Purine De novo

Back 81

-First acquires ribose and then builds purine ring carbon by carbon
-Energy expensive

Front 82

Energy Requirements of purine synthesis de novo

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1 ATP for PRPP
2 ATP for n'-THF
4 ATP for the four steps
==7 ATP for formation of IMP

Front 83

Overview of Pytimidine de novo

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Six member pyrimidine is made first and then attached to ribose 5 phosphate

Front 84

Phosphate exchange reactions

Back 84

Essential reactions for formation of nucleotides.
Know pathways between nucleotides

Front 85

T/F The synthesis of common nucleotides proceed via their free bases

Back 85

FALSE: The synthesis of common nucleotides does NOT proceed via their free bases: the precursor is ALWAYS coupled to ribose

Front 86

What is PRPP

Back 86

5-phosphoribosyl-1-Pyrophosphate is a key activated sugar intermediate

Front 87

What is hypoxanthine?

Back 87

Hypoxanthine is a nitrogenous base and a PURINE RING PRECURSOR that is synthesized stepwise directly on ribose C-1

Front 88

What is orotate?

Back 88

It is a nitrogenous base and carboxylic acid it is synthesized stepwise and THEN attached to ribose C-1