Transcript Chapter 15 Metabolism: Basic concepts and design Part Ⅰ

Chapter 15 Metabolism: Basic concepts and
design
Part Ⅰ:
 the specificity and catalytic power of enzymes
 the regulation of enzyme activity
 the transport of molecules and ions across membranes
Part Ⅱ:
 to extract energy and reducing power from its
environment
 to synthesize the building blocks of its macromolecules
and
then the macromolecules themselves
Metabolism: a highly integrated network of chemical
reactions
 contain many common motifs
§ 15.1 Metabolism is composed of many coupled,
interconnecting reactions
Cells transform different types of
energy
¤ Phototrophs (photsynthetic organisms):
light energy  chemical energy
¤ Chemotrophs:
Utilize chemical energy generated by phototrophs
 ion gradient: other types of chemical energy, nerve
impulses, etc.
 mechanical energy: muscle contraction and movement
 synthesis biomolecules
Metabolism(or intermediary metabolism)
Energy is being extracted from fuels via a linked series chemical
reactions and used it to power biosynthesis processes
Two broad classes:
¤ Catabolism: fuels transform into cellular energy
Fuels (carbohydrates, fats, etc)  CO2+H2O+useful energy
¤ Anabolism:
cellular energy to generate complex structures or energy-rich
compounds
Useful energy + small molecules  complex molecules
* Amphibolic pathways:
either anabolic or catabolic is depended on the energy conditions in
the cell.
Metabolic pathways
– many coupled, interconnecting reactions
§ 15.2 Adenosine triphosphate (ATP)
– the universal currency of free energy in biological systems
(XTP?)
Carbohydrates and fats  ATP
2 Phosphoanhydride bonds
Mg2+ or Mn2+
-4
-2
-3
Pi: orthophosphate
PPi: pyrophosphate
ATP  ADP (ATP-ADP cycle)
the fundamental mode of energy exchange in biological systems
ATP + NDP  ADP + NTP (nucleoside diphosphate kinase)
ATP + NMP  ADP + NDP (nucleoside monophosphate kinase)
ATP + AMP  2 ADP (adenylate kinase, myokinse)
¤ ATP + H2O  ADP + Pi
G0’= -7.3 kcal/mol
ATP + H2O  AMP + PPi G0’= -10.9 kcal/mol
Under typical cellular condition: G = -12 kcal/mol
A+BC+D
G = G0’ + RT ln [C][D]/[A][B]
¤ A thermodynamically unfavorable reaction can be driven by
a favorable reaction  increase a factor of about 108.
Keq of A B under standard condition: 1.15×10-3
Keq of A B under standard condition + ATP: 2.67×102 at pH 7, G°’= -7.3 kcal/mol
Keq of A B under typical cellular condition + ATP : 7.7×105 G= -12 kcal/mol
if nATP 108n
¤ ATP hydrolysis drives metabolism by shifting the equilibrium
of coupling reactions
 chemical energy coupling agent
 protein conformation shift, e.g., muscle contraction
 the conc. of ion or molecule on the outside/inside of a cell,
e.g., Na+/K+ pump
What makes ATP a particular efficient phosphoryl-group
donor
~ P: high energy bond
 The free energy of hydrolysis
 Three structural factors:
1. resonance stabilization,
2. electrostatic repulsion,
3. stabilization due to hydration
ADP and Pi both effectively bind to water than ATP
squiggle (~P) indication
Phosphoryl transfer potential
– an important form of cellular energy transformation
An efficient carrier of phosphoryl groups
High phosphoryl transfer potential compounds
Creatine kinase:
Creatine phosphate + ADP
 ATP + creatine
In vertebrate muscle serves as a reservoir of
high-potential phosphoryl groups
C
Sources of ATP (energy) during exercise
§ 15.3 The oxidation of carbon fuels
 an important source of cellular energy
immediate
energy donor
Chemotrophs
Phototrophs
Free energy of oxidation of single-carbon
compounds
H2
11/20 施明哲主任
Two kinds of trapped energy of fuels oxidation
1. A high-energy phosphate compound
GAP 1,3-BPG  3PGA
 acid
Substrate-level phosphorylation
( p. 443)
2. Ion gradient formation
Three stages of catabolism
§15.4 Metabolic pathways contain many recurring
motifs
¤ Activated carrier of phosphoryl groups, e.g., ATP
¤ Activated carrier of electrons for fuel oxidation
e.g., nicotinamide adenine dinucleotide (NAD+)
flavin adenine dinucleotide (FAD)
¤ Activated carrier of electrons for reductive
biosynthesis
e.g., reduced form of nicotinamide adenine dinucleotide
phosphate
(NADPH)
 NADH is used primarily for the generation of ATP
¤ Activated carrier of two-carbon fragments
e.g., acetyl coenzyme A (CoA)
NAD(P)+: nicotinamide adenine dinucleotide
(phosphate)
Niacin (vit. 3)
(Fig. 15.17)
ADP
H+ + 2eH- (hydride ion)
NADH vs.
NADPH
FAD: flavin adenine dinucleotide
isoalloxazine ring
Vit B2 riboflavin
FMN
5C
Coenzyme A: a carrier of acyl group
thioester
Transfer acetyl group is exergonic
Acetyl CoA carries an activated acetyl group, just as
ATP carries an activated phosphoryl group.
Two key aspects of metabolism utilize activated
carriers:
1. The use of specificity of enzymes to control the flow of free
energy and reducing power, such as NAD(P)H, FADH2
2. The economy and elegance of metabolism underlie design
Lys residue
Act as coenzyme:
are needed in small amounts in the diets
at least 12 vitamins are needed
react with hydroxyl radicals
Vitamins: essential to the health of vertebrates but cannot be
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synthesized, so must be obtained in the diet.
fat-soluble vitamins: A, D, E, K,
all of which are derived from isoprene units
water-soluble vitamins: C, B, biotin, folic acid, nicotinic acid,…
No biological
activity
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Regulate calcium uptake in the intestine and calcium levels
in the kidney and bone
Vitamin D2 (ergocalciferol): is added to milk and butter
Vitamin A (retinol): the visual pigment of the vertebrate eye
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Cure acne and wrinkled skin
p. 424
From fish liver oils, liver, eggs, whole milk, butter
carrots, sweet potato, and other yellow vegetables
β-carotenoids
Deficiency: night blindness, dryness of the skin and eyes…
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Vitamin E:
tocopherols: a substituted aromatic rings and a long isoprenoid
side chain
The aromatic ring reacts with and destroys the reactive oxygen species,
protecting unsaturated fatty acids from oxidation.
Tocopherols: in eggs, vegetable oils, and wheat germ
Vit E deficiency: fragile erythrocytes for humans
scaly skin, muscle weakness and wasting, sterility
Vitamin K:
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active prothrombin formation
Vit. K deficiency: hemorrhagic disease of the newborn
in U.S.A., newborns are injected Vit. K
Vit. K1 rich in green plant leaves
Vit. K2 is formed by the intestinal bacteria
K2: menaquinone
Key reactions are reiterated throughout
metabolism
15.5
p. 237
EC1
oxidoreductase
ligase
EC6
EC5
EC2
EC3
isomerase
transferase
hydrolase
EC4
lyase
p. 427 can proceed in either direction, depending on G and [reactants]
and [products]
Isomerization
aconitase
Glucose isomerase
The addition of functional groups to double bonds
or removal of groups to form double bonds — lyase
aldolase
enolase
The commonalties in the diverse metabolic
pathway
(02)
Metabolic processes are regulated in four principal
ways
1.The amount of enzymes
the rate of synthesis and degradation
the rate of transcription of the genes that encoding enzymes
2. The catalytic activities of enzymes
the reversible allosteric inhibition
CTP inhibit asparate transcarbamoylase
the reversible covalent modification
myristoylation,
phosphorylation, glycosylation, lipidation, methylationpalmitoylation,
prenylation
hormone coordination: epinephrine, insulin
act through 2nd messengers
farnesylation
3. The accessibility of substrates
the flux of substrates among different compartments
compartmentalization (synthesis/degradation)
4. The energy state
Farnesyl transferase inhibitors are a new class of biologically active
anticancer drugs. The exact mechanism of action of this class of
agents is, however, currently unknown. The drugs inhibit
farnesylation of a wide range of target proteins, including Ras. It is
thought that these agents block Ras activation through inhibition of
the enzyme farnesyl transferase, ultimately resulting in cell growth
arrest.
Ubiquitination: lysis protein
Sumoylation: repress gene expression
small ubiquitin-like modifer, SUMO
KXE
Energy charge:
[ATP] + 0.5 [ADP] / {[ATP] + [ADP] + [AMP]}
catabolism
The pH of a cell
anabolism
Phosphorylation potential:
[ATP] / [ADP] [Pi] ex. 11
0.9
Evolution of metabolic pathways
RNA
ribozymes
96 T
97T
96 C
97C
98T