Molecular basis of disease (2)

Question 1

List the main levels of organism coordination

Answer 1

Intracellular, intercellular, intraorganism, interorganism

Question 2

List the 3 main general types of hormonal regulation

Answer 2

Endo- para- auto-crine

Question 3

Name the 3 types of hormones and give examples

Answer 3

Polypeptides (insuline, glucagon)- large, hydrophilic
Amino acid derivatives (adrenaline, noadrenaline)- small hydrophilic/hydrophobic
Steroids (estrogens, glucocorticoids)- small lipophillic

Question 4

Describe the E2 pharmacophore

Answer 4

(6,6,6,5), phenolicA ring, impo but not crucial role of 17-beta-OH group, steroid scaffold not too long

Question 5

Describe the rigid and flexible regions of the estrogen binding cavity

Answer 5

Rigid: mediate recognition of phenolic component of ligand (E2 A-ring) and separation of hydrocyl groups (ligand length).
Flexible: accommodate extensions of ligand core and permit alternate D-ring binding modes.

Question 6

What are the main reasons behind the slow progress in design of NRs selective ligands?

Answer 6

Variability of ligands, over-sized ligand-binding cavities for many other NRs, NR isoforms and hetero-dimerisation, different level of expression of NRs in different tissues and during a lifetime, different co-regulatprs, different levels of co-regulators expression in different tissues.

Question 7

What are the main functions of glucagon?

Answer 7

Glucose synthesis and conversion of glycogen to glucose, ie increasing glucose levels

Question 8

What are the main roles of insulin

Answer 8

Glucose degradation or conversion to glycogen, or use of glucose for uptake into cells or fat synthesis. ie lowering glucose levels

Question 9

What are the 2 types of insulin forms and their roles?

Answer 9

Hexamer= storage, monomer= active

Question 10

Describe the control of insulin release by cell energetics

Answer 10

Glucose transported into cell- respiration produces ATP- ATP:ADP ratio closes K+ channel, depolarisation- influx of Ca2+ ions from voltage gated calcium channel, Ca2+ induces synthesis of insulin and its release, as well as storage of insulin in vesicles which are released into the bloodstream.

Question 11

Describe insulin receptor organisation and its difference from NRs

Answer 11

• binding of insulin to the alpha substitutes causes the beta-subunits to phosphorylate themselves (auto-phosphorylation)- thus activating the catalytic activity of the receptor
• the activated receptor then phosphorylates a number of intracellular proteins, which in turn alters activity, thereby generating a biological response

Question 12

Describe the main steps in insulin signalling which leads to the activation of glycogen synthesis and glucose uptake

Answer 12

In absence of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles where they are useless for transporting glucose.
Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, therby giving the cell an ability to efficiently take up glucose.
When blood levels of insulin decrease and insulin receptors are no longer occupied, glucose receptors are recycled back into the cytoplasm.

Question 13

What is the definition and hallmark of diabetes mellitus?

Answer 13

Metabolic disorder of multiple causes (genetic and environment); hyperglycemia due to ineffective insulin signalling.

Question 14

What is type2 diabetes characterised by?

Answer 14

Hyperglycemia (high blood sugar), fat and protein metabolic alterations that result from defects in the secretion of insulin/ action of insulin/ both

Question 15

What is the end product of fat breakdown?

Answer 15

Acetyl CoA

Question 16

What is acetyl-CoA metabolised to?

Answer 16

‘ketone bodies’- aceto-acetate, beta-hydroxybutyrate, acetone

Question 17

What are the differences between type 1/2 diabetes?

Answer 17

1= insulin dependant, 2= non-insulin dependant

Question 18

What are the main possible reasons for diabetes 1 occurance?

Answer 18

Destruction of pancreatic islet beta-cells by T cells which leads to insulin deficiency

Question 19

What some theories for Typ1 diabetes?

Answer 19

Post-viral infection gives autoimmunity to enzymes in pancreas, insulin is an antigen itself

Question 20

What is type 2 diabetes characterised by?

Answer 20

High blood and urine glucose levels that are RESISTANT TO INSULIN, unable to push glucose into fat, patients tend to be obese

Question 21

What are some theories behind type 2 diabetes onset?

Answer 21

1. Phosphorylation of IR Substrate (IRS) by fatty-acid-induced pathways leads to Insulin
   in-sensitivity
2. 2. Fat cells (adipose tissue) can release many biologically active molecules and
      proteins (it’s very ‘endocrine’ active!!!):
3. the role of adipose tissue (fat) stems from the fact that the organ is active at secretion of
   cytokines, termed adipo-cytokines – they contradict insulin actions.
4. These include tumour necrosis factor-a (TNFa), interleukin-6 IL-6), leptin, adiponectin
   and resistin.
5. 3. Multi-Genetic background of NIDMM:
6. Maturity Onset type Diabetes of the Young (MODY) was previously considered to be a
   third form of type 2 diabetes: mutations in at least 6 genes of some transcription factors

Question 22

What are the 3 types of clinical insulin analogues?

Answer 22

normal(basal)- mimic normal insulins to avoid hyper/hypo glycemia
rapid- to avoid hyperglycemia, to act immediately after the meal:
-monomeric = disruption of dimer interfaces by single amino acid
mutation:
-swap B28-B29 amino acids (insulin LysPro)
-mutation B28Pro into Asp
long acting- to avoid hypoglycemia: poglycemia
(a) Modify the B-chain to achieve molecular ‘stickiness’ of insulin:
- fatty acids attachment to LysB29
(a) To increase pI of insulin = make it more insoluble:

Question 23

List some possible chemical modifications of insulins

Answer 23

N-peptide methylation, D-amino acids, loss of C-alpha chirality

Question 24

What is adipose tissue differentiation?

Answer 24

Complex cascade of gene expression regulated by a small set of transcription factors

Question 25

List the roles of nuclear receptors in T2DM

Answer 25

• PPAR (Peroxisome Proliferator-Activated Receptor)
• NRs that are “scavengers” for lipid metabolites
• key factor in adipose proliferation and differentiation
• can be stimulated by thiazolidinediones (TZDs)
• TZDs are anti-diabetic drugs (PPARgamma2 agonists):
• stimulate synthesis of more adipose tissue and its differentiation:

Question 26

What is a neoplasm (cancer)?

Answer 26

new growth, autonomous

Question 27

Describe the differences between simple and complex diseases

Answer 27

‘Simple’ diseases there is a close relationship between the disease gene and the disease
status. GENOTYPE and PHENOTYPE are closely correlated
– Mutations CAUSE the disease.
–
• Complex diseases also show genetic involvement but the relationships between a
particular gene and the disease is less clear cut. GENOTYPE and PHENOTYPE show
poor correlation.
– Mutations PREDISPOSE to a disease

Question 28

What do tumour suppressor genes control?

Answer 28

Cell cycle progression

Question 29

List some tumour suprressors

Answer 29

-The Rb retinoblastoma susceptibility gene (retinoblastoma, osteosarcoma)
-The p53 cell cycle control gene (numerous cancers)
-The p16 (INK4) gene (melanoma, pancreatic cancer, other c.)
-The familial BReast CAncer susceptibility genes (BRCA1-2: breast cancer, ovarian cancer,
prostate cancer)
-The Adenomatous Polyposis Coli (APC) gene (colorectal cancer, adrenal carcinomas, brain
tumors, other c.)

Question 30

What are the BCRA1/ BCRA2 nuclear proteins involved with?

Answer 30

DNA repair (ds DNA)