Biochem - Exam 3

Question 1

What are the sequelae of classical inborn errors of metabolism involving a missing or defective pathway?

Answer 1

1. Decreased production of product B
2. Accumulation of metabolite A
3. Increased formation of other metabolites C

Question 2

What non-specific symptoms to babies frequently display if they have a disorder involving a central metabolic pathway?

Answer 2

• vomiting
• lethargy
• poor feeding
• fitting
• hypotonia

Question 3

How are amino acids catabolized?

Answer 3

Phase 1:
Removal of the alpha-amino group
Some free ammonia excreted in urine but most converted to urea

Phase 2:
Carbon skeleton converted to intermediates and converted to energy through metabolism

Question 4

What enzyme and cofactor is required to convert amino acid to keto acid (i.e. to strip amino group)?

Answer 4

Enzyme: amino transferase

Cofactor: PLP

Question 5

What is the relevant reaction involved in PKU?

Answer 5

Conversion of phenylalanine to tyrosine
Enzyme: phenylalanine hydroxylase
Co-factor: tetrahydrobiopterin

Question 6

What is tetrahydrobiopterin converted to during the converted to as a co-factor in the phenylalanine to tyrosine reaction? And what is the enzyme used to convert it back?

Answer 6

Dihydrobiopterin.

Enzyme: dihydrobiopterin reductase

Question 7

What happens if phenylalanine accumulates due to PKU?

Answer 7

It is converted to phenylpyrivate.
Enzyme: aminotransferase
Co-factor: PLP

Then phenylacetate and phenyllactate.

Question 8

What is lactose broken down into?

Answer 8

D-galactose and D-glucose

Enzyme: lactase

Question 9

What is Galactose converted to and what is the enzyme?

Answer 9

Galactose-phosphate

Enzyme: galactokinase

Question 10

What will a deficiency in galactokinase result in?

Answer 10

Galactose accumulation

Question 11

What does thyroid hormone synthesis required?

Answer 11

Sufficient dietary iodine

Question 12

What are the two biologically active thyroid hormones? What are they converted from?

Answer 12

Both converted from tyrosine residues on thyroglobulin to form iodinated tyrosine residues which are converted to a) and b) via proteolysis.

a) T4 – tetraiodothyronine (‘thyroxine’)
- 2 tyrosine + 4I

b) T3 – triiodothyronine
- 3 tyrosine + 3I

Question 13

In terms of cell cues, why do cancer cells have uncontrolled survival and proliferation?

Answer 13

Both death cues and growth inhibition cues are inhibited, whereas survival cues and proliferation cues are self-generated.

Question 14

What complexes drive cell cycle from one step to the other?

Answer 14

CDK-cyclin complexes. Can be inhibited or activated to control the cell cycle.

Question 15

How does Rb regulate cell cycle?

Answer 15

It prevents activation of E2F transcription factor.

Cdk2 cyclin A inactivates Rb so that EF2 can be released

Question 16

What INTERcellular signal promotes cell division?

Answer 16

Mitogens (growth factors)

Some mitogens activate receptor tyrosine kinase. This initiates a signal transduction pathway tha leads to the expression of G1 cyclin D genes.

Question 17

In terms of intercellular signals, what are cell cycle negative controls?

Answer 17

Protein ligands known to inhibit cell division when growth is not necessary

Question 18

When is TGF-beta secreted and what does it do?

Answer 18

A ligand secreted under growth-inhibitory conditions.

Binding to its receptor, it initiates a signaling cascade which eventually blocks phosphorylation and inactivation of Rb. Blocking Rb inactivation means that E2F will remain inactivated by Rb, and DNA replication cannot proceed. The cell cycle is switched off.

Question 19

How can a cell initiate apoptosis in a neighbouring cell?

Answer 19

A membrane bound protein called FasL protrudes from the cell surface.

Its presence is a signal to the adjacent cell to self-destruct.

FasL binds to 3 Fas receptors (a trimer) on the neighboring cell. Trimerisation of cytoplasmic domains activated a molecule called Apaf, which activated an initiator caspase. This leads to cell death.

Question 20

What do cancer promoting mutations do?

Answer 20

a. Increase ability of cell to proliferate;
b. Decrease susceptibility of cell to apoptosis;
c. Increase general mutation rate in cell or its longevity


Question 21

What causes cancer?

Answer 21

An accumulation of mutations that leads to uncontrolled proliferation.

Question 22

What are the two general kinds of mutations associated with tumors?

Answer 22

1. Oncogene mutations
   - gain of function
   - mutation only required in one allele
   - gene in its normal unmutated form = proto-oncogene
   - proto-oncogenes normally produce factors that stimulate cell division. They regulate notmal cell proliferation or apoptosis.
   - Oncogene active even in absence of signal, leading to an increased rate of proliferation or prevention of apoptosis.
2. Tumor suppressor gene mutations
   - loss of function
   - both alleles must be mutated and have no activity
   - tumor suppressor genes usually produce factors that inhibito cell division i.e. arrest cell cycle or induce apoptosis. If mutated, cells lose ‘brake’ that can stop cell proliferation.
   - i.e. p53

Question 23

What is the consequence of being heterozygous for a tumor-suppressor gene?

Answer 23

These people are predisposed to cancer.

Question 24

Why do mutations decreasing apoptosis cause tumors?

Answer 24

The cell has a much longer lifetime. More chance of accumulating proliferating-promoting mutations. When these mutations take place, the cell would usually induce apoptosis but in this case it can’t.

Question 25

What are some of the types of mutations that could cause an oncogene?

Answer 25

• point mutations that alter structure/function
• deletions that result in loss of protein domains
• gene fusions, often resulting from translocations
• sometimes mutations result in mis-expression, with proteins expressed in the wrong place or time

Question 26

What is an example of an oncogene caused by gene fusion?

Answer 26

Brc1-abl fusion onco-protein - Chronic myelogenous leukaemia.

Structurally altered oncoprotein caused by gene fusion. The abnormality is termed ‘Philadelphia chromosome’ or ‘Philadelphia translocation’ and is caused by a translocation between Chromosome 9 and 22.

Result: onco-protein causes permanent protein kinase activity. Chronic myelogenous leukaemia.

Question 27

What is an example of a tumor-suppressor gene mutation?

Answer 27

P53 mutation

Normal p53 is a transcription factor that is activated in response to DNA damage. It prevents cell cycle progression to allow repair and causes severely damaged cells to undergo apoptosis.
The mutated form eliminates apoptotic response, allowing damaged cells to survive and therefore elevating mutation level.

~50% of all tumors have mutated p53

Question 28

What are some of the viruses associated with cancer?

Answer 28

a) Retroviruses
- mutates and rearranges proto-oncogenes
- inserts strong promoters near proto-oncogenes

b) HPV:
- causes cervical cancer by inactivating Rb and p53

c) EBV
- Burkitts lymphoma

d) HTLV-1
- T cell leukaemia