Chapt. 21 Metabolic coordination and control

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.