chapter 15 metabolism: basic concepts and design part Ⅰ : the specificity and catalytic power of...
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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
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
§ 15.1 Metabolism is composed of many coupled, interconnecting reactions
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.
Biosynthetic and degradative pathways are always distinct.
§ 15.2 Adenosine triphosphate (ATP) – the universal currency of free energy in biological systems
(XTP?)
2 Phosphoanhydride bonds
Mg2+ or Mn2+
-4 -3
-2
Carbohydrates and fats ATP
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
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
~ P: high energy bond
Phosphoryl transfer potential – an important form of cellular energy transformation
An efficient carrier of phosphoryl groups
High phosphoryl transfer potential compounds
C
Creatine kinase:
Creatine phosphate + ADP
ATP + creatine
In vertebrate muscle serves as a reservoir of high-potential phosphoryl groups
Chemotrophs
Phototrophs
immediate energy donor
§ 15.3 The oxidation of carbon fuels
an important source of cellular energy
Two kinds of trapped energy of fuels oxidation
1. A high-energy phosphate compound
GAP 1,3-BPG 3PGA
2. Ion gradient formation
Substrate-level phosphorylation
( p. 443)
acid
§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+ + 2e-
H- (hydride ion)NADH vs. NADPH
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
Vitamins: essential to the health of vertebrates but cannot be
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
Nelson
Regulate calcium uptake in the intestine and calcium levels
in the kidney and bone
Vitamin D2 (ergocalciferol): is added to milk and butter
Nelson
Vitamin A (retinol): the visual pigment of the vertebrate eye
β-carotenoids
Cure acne and wrinkled skin
From fish liver oils, liver, eggs, whole milk, butter
carrots, sweet potato, and other yellow vegetables
Deficiency: night blindness, dryness of the skin and eyes…
Nelson
p. 424
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
Nelson
Vitamin K:
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
Nelson
K2: menaquinone
Key reactions are reiterated throughout metabolism
EC1
EC6
EC5
EC2
EC3
EC4
oxidoreductaseligase
isomerase
transferase
hydrolase
lyase
p. 427 can proceed in either direction, depending on G and [reactants]
and [products]
p. 237
15.5
The addition of functional groups to double bonds or removal of groups to form double bonds — lyase
aldolase
enolase
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
phosphorylation, glycosylation, lipidation, methylation
hormone coordination: epinephrine, insulin
act through 2nd messengers
3. The accessibility of substrates the flux of substrates among different compartments
compartmentalization (synthesis/degradation)
4. The energy state
myristoylation, palmitoylation,prenylation
farnesylation
Ubiquitination: lysis protein
Sumoylation: repress gene expression
small ubiquitin-like modifer, SUMO
KXE
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.
Energy charge: [ATP] + 0.5 [ADP] / {[ATP] + [ADP] + [AMP]}
catabolism
anabolism
0.9
The pH of a cell
Phosphorylation potential:
[ATP] / [ADP] [Pi] ex. 11