General observations
for a review:
1. ATP is used
as universal currency
2. Glucose,
fat, aminoacids are fuels
3. NADPH is
needed for biosynthesis
4. Many small
molecules are needed (diversity)
5. Catabolic
and anabolic pathways compared
6. Tissue-specific
metabolisms differ
Issues of metabolic
regulation; know examples
1. allosteric
control
2. covalent
modifications
3. enzyme levels
4. compartmentation
Major pathways
of fuel metabolism in mammals, Fig. 21-1
Metabolic interactions
among major fuel-metabolizing organs, 21-2
Key organ:
liver.
Utilization of carbohydrate nutrients;21-3,21-4
Aminoacids
metabolism in liver. Fatty acids metabolism. Liver has glycerol kinase!
Main concerns
of muscle; it does not release glucose; but provides lactate, Ala
Cooperation
between muscle and liver,21-5 Cori Cycle; glucose -Ala cycle, 21-6
Adipose
tissue-
special functions. Needs glycolysis to make glycerol-P
Brain-
its nutritional needs
Blood
Glucose transporters.Insulin
dependent Glut4 transporter:21-7
HORMONES
Multiple roles
in homeostasis, response to external stimuli, development,
Endocrine systems;
Fig. 21-8,
Definition,
history. Chemical classification. Examples of
peptide
hormones
insulin,
glucagon, ACTH,TSH,FSH,LH,GH
vasopressin,
oxytocin, secretin, angiotensin
cholecystokinin
steroid
hormones
mineralocorticoids:
aldosterone
glucocorticoids:
cortisol
sex
hormones: testosterone, estrogen, progesterone
amine hormones
thyroxin,
epinephrine
eicosanoids
Prohormones;
General
mechanisms of hormone action; signal
transduction systems
The receptor;
beta-adrenergic, Fig. 21-10
The Cyclic
AMP Pathway
Adenylyl cyclase
rxn; cyclic phosphodiesterase
activators,
inhibitors
Activation
of adenylate cyclase, Fig. 21.12; Gs and Gi proteins
The Gs protein
structure and cycle, 21-11
Properties
of mammalian G proteins,
Box 21-1
Diseases; cholera
toxin, B. pertussis; ADP-ribosylation
Cyclic GMP,
type I and
type
II, soluble; role of NO; nitroglycerin
angina,
impotence and viagra
Ca- inositol-P
pathway
G protein,
phospholipase C, second messengers: IP3, DG; proteinkinase CFig. 21-18,
21-19
Receptor
Tyrosine Kinases, RTKs
Growth hormone
receptor, 21-13
EGF, FGF, CSF-1,
IGF-1; Fig. 21-14: SH2 domain
Activation
via dimerization: Fig. 21-15
Role of ras
protein in a central growth factor activating pathway, 21-16
Review of the
Big 3 Regulators of Fuel Metabolism;
Epinephrinephysiological
and metabolic effects
molecular
mechanism
Glucagonmetabolic
and molecular changes;
Insulinmetabolic
effects, target enzymes; receptor 21-17
diabetes;
IDDM, NIDDM. Metabolic abnormalities in diabetes;
Hormones and
gene expression
Steroid and
thyroid hormones enter cells
Protooncogens,
oncogens, Box 21-2
Oncogen products
and signal transduction,
Human tumors,
and ras protein;
Obesity and
leptins
Chapt.
22: NUCLEOTIDE METABOLISM
Degradation
of nucleic acids (not in the textbook): DNAases, RNAases to oligonucleotides;
Nucleotidase;
nucleoside phosphorylases, hydrolases; phosphoribosyltransferase
Origin of atoms
in purine and pyrimidine
The role of
PRPP, PRPP synthetase in de novo and salvage synthesis,
De novo
purine synthesis : Fig.22.1
Committed step:
rxn of PRPP with Gln
IMP is bifurcation
point to AMP and GMP , Fig. 22-3
Feedback control
mechanisms, Fig. 22-4
Pyrimidine
nucleotide biosynthesis; Fig.22.10
Study all steps;
emphasis 1st step, Fig. 22-5
Asp+carbamoyl-P-----
carbamoyl-aspartate +P
enzyme:ATCase;
its regulation, Fig. 22-7
UTP to CTP
conversion, Fig. 22-6
Kinases; NMP---NDP---NTP
equilibrium
Synthesis
of deoxyribonucleotides.
Structure of
the reductase enzyme; 22.8; mechanism: 22.9
The flow of
electron: (thioredoxin,22-10, glutaredoxin)22.11
The role of
dUTPase: producing dUMP
The thymidylate
synthase reaction; 22.14
Dual
role of methylene FH4; CH2OH intermediate, Fig. 22-15
Degradation
of nucleotides
5'-nucleotidase:
is a spec. phosphatase
Deaminases
exist at all 3 levels (base, nucleoside, nucleotide)
Nucleosideses
are hydrolytic enzymes that split N-glycoside
The "salvage"
enzymes are also involved in catabolism
Xanthine oxidase
rxns; xanthine, uric acid, Fig. 22-17
Salvage
pathways
2 types: pyrophosphorylase
and phosphorylase
adenosine phosphoribosyltransferase
and HGPRT
Diseases: Lesch-Nyhan
syndrom
adenosine deaminase
deficiency: imunodeficiency
Gout: treatment
with allopurinol. Fate of uric acid: 22-21
Chemotherapeutic
concepts; rational drug design. Box 22-1
Nucleotide
antimetabolites; suicide inhibitors
Inactive precursors--biotransformation
to the toxic/active form
5-F-uracil,
AZT, ara-C, ara-A, acyclovir, dideoxynucleosides
Role in cancer,and
virus(HIV) therapy.
Active form
often the triphosphate of the analog, which
inhibits polymerase;
incorporation, chain termination possible
Homework
challenge for practice purposes (no bonus pts.If
the exam were the open book type, you would have such problems)
Imagine that
you are going to discover how deoxyribo-
nucleotides
are synthesized in bacteria. You will use
radioactive
labels in your suspected starting materials, but
you have no
[14C]-deoxyribose. Only the neutral compounds
are taken up
in vivo. The expectation that the pathway to deoxynucleotides is
similar to
the ribonucleotide synthesis (with the only difference
of starting
with PdRPP) will be proven wrong.
You find that
when labeled adenosine is applied, both
RNA and DNA
become labeled. Give an outline compatible
with this finding.
You must exclude
the possibility that adenosine could be
hydrolized
in vivo to adenine and ribose (or AMP to ade + PR);
and the resulting
ribose or ribose phosphate would be reduced
to deoxyribose
or PdR, which then could be combined with
adenine and
other bases via a salvage pathway. This is the
main task:
how do you prove that the N-glycosidic linkage
remains intact
throughout the process?
Devise an experiment
that provides unrefutable proof
that the adenosine
derivative is reduced directly. You have
no purified
enzyme and suitable cell-free system at your disposal.
This problem
is based on a typical example, a typical
situation of
biochemical research on pathways, when questions
are raised,
hypotheses are made, some of which are proven
or disproven.