1 - Basic Concepts in Metabolism Flashcards
(63 cards)
1
Q
Typical Enzymes
A
-
Not a Drug Target:
-
Lysosyme
- hydrolyzes bacterial cell wall
-
Lysosyme
-
Drug Targets
-
Lactate Dehydrogenase
- Lactate -> Pyruvate
-
Carbonic Anhydrase
- CO2 -> Bicarbonate
-
Orotidine Decarboxylase
- Greatest Rate of ACCELERATION/enhancement
-
Lactate Dehydrogenase
2
Q
6 Main Enzyme Classes
A
- Oxidoreductases
- Transferases
- Hydrolases
- Lyases
- Isomerases
- Ligases
3
Q
Oxidoreductases
A
Redox Reactions
Lactate dehydrogenase
4
Q
Transferases
A
Move Chemical Group
Creatine KINASE
Alanine aminotransferase
5
Q
Hydrolases
A
Hydrolysis
Bond cleavage w/ xfer of
fxn group –> Water
Lysosyme
Chymotrypsin
6
Q
Lyases
A
Non-hydrolytic bond cleavage
Addition of groups across a DOUBLE BOND
Fumerase
7
Q
Isomerases
A
Intramolecular group transfer
–> change in spatial geometry
Triose Phospate isomerase
Methylmalonyl CoA mutase
8
Q
Ligases
A
formation of New covalent bond
between substrates using NTP Hydrolysis
RNA polymerase
Pyruvate carboxylase
9
Q
Enzyme Sub-Classes
A
Used to describe the different
Enzyme-catalyzed rxns
Amoung the PROTEINS catalyzing them
10
Q
Isozyme
A
Catalyze the SAME rxn but differ in AA Sequence
Allows for FLEXIBILITY & CONTROl
-
Differ in catalytic activity / cofactor / regulation
- Encoded by diff genes
- Expressed at different stages of development / tissue
- Across components
-
Lactate Dehydrogenase
- 5 different Isozymes
*
- 5 different Isozymes
11
Q
Cofactors
A
Small organic/inorganic molecule or ions
to ASSIST IN CATALYSIS
-
Dietary intake of vitamins & Minerals (IRON)
- __most can be synthesized by humans
- tetrapyrrole ring of heme groups
- but many need to be chemically modified first
- __most can be synthesized by humans
12
Q
CoEnzymes
Type of Cofactor
A
- Held LOOSELY by enzymes
- Rxn –> Release –> Recycled (by a different set of enzymes)
- NADH / CoA
13
Q
Prosthetic Groups
Type of Cofactor
A
- Held “TIGHTLY” by enzymes
- Recycled when IN PLACE
- Heme / Flavin / Fe-S centers
14
Q
Catabolic Pathway
A
Break DOWN complex precursors –> simple products
Make Energy
Can occur in the same or different place as anabolism
- Proteins -> AA
- FA -> Acetyl-CoA
- Carbs -> CO2 + H2O
15
Q
Anabolic / Biosynthetic
A
BUILD UP –> Complex Products
USE ENERGY
Can occur in the same or different place as catabolism
- AA -> Protein
- Acetyl-CoA -> Lipids
16
Q
Glycolysis
A
Glucose -> Pyruvate
Cytosol
17
Q
Fatty Acid Oxidation
A
FFA -> Acetyl-CoA
MITO
18
Q
Amino Acid Catabolism
A
AA -> Ketoacids + Urea
MITO
19
Q
TCA Cycle
A
Pyruvate -> Acetyl-CoA -> NADPH
Mitochondrial MATRIX
20
Q
Oxidative Phosphorylation
A
ATP Synthase
NADH -> ATP
Mitochondrial MEMBRANE
21
Q
Urea Cycle
A
AA -> Ammonia -> UREA
Cytosol->MITO
22
Q
Glycogenesis
A
Glycogen Synthesis
Glucose –> GLYCOGEN
CYTO of muscle/liver/adipose
23
Q
Glycogenolysis
A
Glycogen Breakdown
Glycogen -> GLUCOSE
CYTO of muscle/liver/adipose
24
Q
Gluconeogenesis
A
AA / TG / Glycerol -> GLUCOSE
Production of GLUCOSE by non-carbohydrates
Cytosol + Mitochondria
25
**Lipogenesis**
**Fatty Acid Synthesis**
**Acetyl-CoA --\> FFA**
_CYTOSOL_
26
**Triglyceride Synthesis**
**FFA + Glycerol --\> TG's**
_Cytosol_
27
**Amino Acid Synthesis**
**Nitrogenous Molecoles -\> AA**
**_Mitochondria_**
28
**Porphyrin Synthesis**
**Heme Synthesis**
**Glycine + Succinyl-CoA -\> HEME**
**_Mito + Cyto_**
29
**Mevalonate Pathway**
**Cholesterol + Steroid Synthesis**
Acetyl-CoA -\> Cholesterol
**_CYTOSOL_**
30
**Nucleotide Synthesis**
**Phosphate + Sugar + N-Base -\> NUCLEOTIDE**
_Both Cyto/mito_
31
**Catabolic Funnel Stages**
1. **Complex Molecules -\> Monomers**
1. Fats / Polysacchrides / Proteins
2. **Monomers -\> Simple Intermediates**
1. ****--\> Acetyl-CoA
3. **Produce Energy**
1. ****TCA Cycle + Oxidative phosporylation
1. Recycles cofactors
32
**Committing Step**
**First Unique Step**
Typically the natural choice for a point of REGULATION
**_PFK-1_** = first unique step in Glycolysis
33
**How to decide on which step we should regulate**
* Target the **MOST EFFICIENT SITE** (typically most unique)
* **Junctions of metabolic/signaling paths**
* *Not just the start or the unique step*
* _Glycolysis - G6K step is also used in_
* _spinal/sensory neurons outide of the cell_
34
**PFK-1**
**Committing Step of Glycolysis**
NOT used in any other pathways
**F6K -\> F1,6Bisphosphate**
35
**Sites of Glycolysis Regulation**
**PFK-1 =** commiting step
HEXOKINASE (Start)
Glucose -\> G6P
PYRUVATE KINASE (end)
-\> Pyruvate
36
**3 (6) Basic Ideas for**
**Maintaining Metabolic Homeostasis**
1. **Feedback**
2. **Crossover Theorem**
3. **Energy Charge**
4. Compartmentalization
5. Tissue Communication / signal transduction
6. Energy Regulation
37
**Tisssue Communication / Signal Transduction**
Maintaining Metabolic Homeostasis
**_Hormones / Cytokines / Nervous System_**
used to Maintain Metabolic Homeostasis
38
**Feedback**
Maintaining Metabolic Homeostasis
Returns a portion of the **Output of a system as an INPUT**
**_Typically is NEGATIVE FEEDBACK_**
39
**Negative Feedback**
**Returns the system to the STATUS QUO**
**MAINTAIN HOMEOSTASIS**__
_ATP -/-\> Glycolysis_
_UTP + CTP -/-\> Pyrimidine synthesis_
_Contraction of iris in eye in bright light_
40
**Positive Feedback**
**Can be DANGEROUS -\> Runaway reactions**
relatively rare in metabolism
_Microphone shriek_
_Cancer_
41
**Crossover Theorem**
* Activating or inhibiting an enzyme in a pathway will result in:
* Changes in the metabolite concentrations before & after that step
* **Changes occur in opposite directions**
* **_PKU_**
* MORE PKU -\> Drop in TYR production
* but also a rise in the metabolites of PHE
42
**Phenylalanine Hydroxylase**
**Phe + BH4 -\> Tyr**
BH4 is a COFACTOR for the enzyme
43
**Dihydrobiopterin Reductase**
**BH2 + NADPH -\> BH4**
**_BH4 is a needed cofactor for Phenylalanine Hydroxylase_**
( Phe -\> Tyr )
44
**Phenylketouria**
**PKU**
**Lack of Phenylalanine Hydroxylase**
**Phe -/-\> Tyr**
* **Tyrosine becomes Essential**
* used for _Catacholamines (hormones + NTs)_
* __**-\> Mental Retardation / Neurological Upsets**
* **Build up of Phe & its unusual metabolites**
* ****"Cross over Theorem"
* + phenylacetate
45
**Varient PKU**
**Defects in metabolism of BH4**
Treated with **BH4 supplement**
BH4 needed for Phenylalanine Hydroxylase
+ _L-Dopa & 5 hydroxytryptophan for NT synthesis_
46
**PKU Diagnosis + Treatment**
**Lab Test on blood / Urine (Mass Spec)**
* Dietary Interventions:
* **Supplement Tyrosine**
* ***Restrict intake of Phe***
* ***Avoid protein rich foods, Aspartame***
47
**HMG-CoA Reductase**
**Comitting step in Cholesterol Synthesis**
* **Statin** Inhibition exploits the _Cross Over Theorem_
* Leads to less cholesterol
* HMG-CoA -\> Mevalonic Acid -\>-\>-\> Cholesterol
48
**Energy Charge**
**EC**
Maintaining Metabolic Homeostasis
Ratio of **Available Phosphoanhydrade Linkages**
## Footnote
**ATP + 1/2 ADP**
**----------------**
**ATP + ADP + AMP**
**Entire pool of adenine nucleotides**
**_Higher when MORE ENERGY is available for Work_**
49
**Energy Charge Graph**
* **Steepest Parts = Most sensative to changes in EC**
* **_0.80 - 0.95 for most cells_**
* **HIGH EC**
* *****inhibits pathways GENERATING ENERGY*
* STIMULATES pathways that consume energy
50
**Glycolysis Regulation @ PFK-1**
* **Stimulated by:**
* **_ADP / AMP / cAMP / Fructose 2,6-bisP_**
* **__**PFK-2 forms F26BP but is not in glycolysis
* This is a rare example of POSITIVE FEEDBACK
* **__*Inhibited by:***
* ***ATP & Citrate***
* ***NEGATIVE FEEDBACK*********
51
**Compatmentalization**
Maintaining Metabolic Homeostasis
**Major OPPOSING pathways are often located in DIFFERENT intracellular compartments**
_membrane barriers / special transport systems_
* Compartments allow for control of:
* **Concentrations**
* **Seperation of competting processes**
* ****_Fatty Acid Oxidation in MITO_____
* _Fatty Acid Syntheis in CYTO_
52
**Regulation of Enzymes**
Maintaining Metabolic Homeostasis
Control **Concentration** of Materials W/
**_Enzymes / Substrates / Cofactors / Products_**
**_Isozymes_** for flexibility
**Enzymes Activation/deactivation**
53
**Covalent Modification**
Ways to Activate / Deactivate Enzymes
Often used in **Signaling Cascades**
Can be **_Reversible or Not_**
1. **Phosphorylation**
2. **Acetylation**
3. **Proteolytic Processing**
4. **Glycosylation**
5. Adenylation
6. Methylation
54
**Reversible Non-Covalent Modifications**
Ways to Activate / Deactivate Enzymes
**Allosteric Effectors**
Often the effector concentation is connected to overall metabolic state of cell
55
**Phosphorylation**
Covalent Modification
**Sensitive to EC**
**Phosphate -\> OH**
of _Ser Thr Tyr_
56
**Acetylation / Acylation**
Covalent Modification
Sensitive to Metabolic State of Cell
**Acetyl -\> OH**
_of Ser / Thr_
**Fatty Acid (Acyl) -\> Direct protein**
like inserrtion in a membrane
57
**Proteolysis / Proteolytic Cleavage**
Covalent Modification
**Activate _Proenzymes / Pro-hormones_**
Deactivate / Recycle **_Mature proteins / peptides / enzymes_**
**_INSULIN_** needs to be proteolytically activated
58
**Glycosylation**
Covalent Modification
**Sugar -\> Protein Site**
Used in **TARGETING** the protein to a cell location
or in **PROTECTION** in cleavage / denaturing agents
59
**Allosterism**
**Change Shape & Activity**
**R Form = Active**
* **_ATCase_**
* key enzyme in PYRIMIDINE Synthesis
* responds to effectors & contraolled by allosterism
* **_Hemogloblin_**
* **__**Oxygen transporter
* Changes shape upon Oxygen uptake/release
60
**R Form**
Allosterism
**Active & Open**
conformation
61
**T Form**
Allosterism
***LESS Active***
conformation
62
**Reciprocal Regulation**
Cell will contain enzymes for both
**Synthysizing & Breaking down**
the same set of biochemical compounds
* Leads to **PROBLEMS if in SAME COMPARTMENT**
* *****Waste of energy / resources*
* *Loss of time*
* **--\> **_subcellular organelles w/ specialization_**
63
**How to Achieve Homeostasis**
* Use Two of the main control mechanisms
* **Covalent Modification**
* **NonCovalent binding of small efector molecules**
* ****To alter activity
* Can be employed at the SAME TIME
* --\> Regulate a PAIR of competing pathways
* Ex.
* _Glycogen synthesis & breakdown_
* _AA synth/breakdown_
