M2M Test 1 diseases and medicine

Question 1

Gout and Lesch-Nyhan Disease

Answer 1

Defects in hypoxanthine-guanine phosphoribosyl transferase, which will ultimately lead to defects in Uric Acid
Lead to the accumulation in tissues of purines of low solubility.

Question 2

AZT, DDI drugs (azidothymidine and dideoxyinosine)

Answer 2

o These drugs are chain terminators (used as antiretroviral) to go against retroviruses like HIV
o AZT and DDI inhibits the enzyme (reverse transcriptase) that HIV uses to synthesize DNA, thus preventing viral DNA from forming.
They are chain nucleosides (lack the phosphates) which the 2’ and 3’ carbon hydroxyl group are absent

Question 3

Doxorubicin (drug)

Answer 3

Doxorubicin is a drug used in cancer chemotherapy (via intercalcation) and derived by chemical semisynthesis from a bacterial species.
It blocks DNA replication with its massive structure that’s intercalated =stops synthesis of Cancer DNA

Question 4

Methyltransferase (MGMT)

Answer 4

o Enzyme: Removes a methyl group from methylguanine returning it back to normal guanine
If cancer mutates this enzyme, things go bad with it silenced or not working
o Is considered a “Direct Reversal” Type of DNA repair, is very specific

Question 5

HNPPC (Hereditary nonpolyposis colorectal cancer) or Lynch’s Syndrome

Answer 5

It is a type of Colon Cancer, It is caused by a mutation in mismatch repair (the type of DNA repair after replication).The hallmark of HNPCC is defective DNA mismatch repair, which leads to microsatellite instability,

Question 6

PARP- Poly(ADP-ribose) Polymerase enzyme

Answer 6

• Activated by single strand break
• Will release signals that there is broken single strand of DNA
• Will lead to enrichment of repairing proteins

Question 7

Alpha Amanitin

Answer 7

A cyclic peptide that inhibits and stops the function of RNA Polymerase II, by inhibiting the bridge jaw/ bridge helix of the RNA Polymerase.It is possibly the most deadly of all the amatoxins, toxins found in several species of the Amanita genus of mushrooms, one being the death cap.

Question 8

Rifampicin

Answer 8

Antibiotic: targets bacterial polymerase, blocks the exit channel for RNA strands when they are made

Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically blocking the formation of the phosphodiester bond in the RNA backbone

Most bacterias develop strong antibiotic resistance to Rifampicin- most often via pump.

Question 9

Thalassemia

Answer 9

Thalassemia is a form of inherited autosomal recessive blood disorder characterized by abnormal formation of hemoglobin. Thalassemia is caused by variant or missing genes that affect how the body makes hemoglobin, the protein in red blood cells that carries oxygen.

The abnormal hemoglobin formed results in improper oxygen transport and destruction of red blood cells.
Both α- and β-thalassemias are often inherited in an autosomal recessive manner. Cases of dominantly inherited α- and β-thalassemias have been reported, the first of which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene.

Question 10

Hemophillia B-Leyden

Answer 10

is a blood clotting disorder caused by a mutation of the factor IX gene, leading to a deficiency of factor IX.

• Transcription factors/activators not binding around Promoter properly
• At puberty, when androgen receptor site becomes active, it can bind at the promoter site and increase transcription, leading to the necessary expression for factor IX functionality.
• Is an X-linked Disorder

Question 11

Fragile X Syndrome

Answer 11

Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome.

It is an inherited cause of intellectual disability especially among boys. It results in a spectrum of intellectual disabilities ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and large testes (macroorchidism), and behavioral characteristics such as stereotypic movements (e.g. hand-flapping), and social anxiety.

As a result, this part of the FMR1 gene is methylated, which silences the gene (it is turned off and does not make any protein). Without adequate FMRP, severe learning deficits or mental retardation can develop, along with physical abnormalities seen in fragile X syndrome.

Question 12

Homeodomain proteins (Helix Turn Helix)

Answer 12

Members include the Hox family, Pit1, Msx

Only one not involved with Dimer formation.

These genes encode homeodomain protein products that are transcription factors sharing a characteristic protein fold structure that binds DNA

Craniosyntosis happens with a Homeodomain mutation.

Question 13

Zinc Fingers

Answer 13

Members included nuclear receptors such as estrogen receptor, androgen receptor, and retinoic acid receptors

The Cys2His2-like fold group is by far the best-characterized class of zinc fingers and are extremely common in mammalian transcription factors.

Question 14

Basic Leucine Zipper (bZIP)

Answer 14

A class of eukaryotic transcription factors.[3] The bZIP domains is 60 to 80 amino acids in length with a highly conserved DNA binding basic region and it has that name because leucines occur every seven amino acids in the dimerization domain.

Members include c-fos and c-jun

Question 15

Basic Helix Loop helix (bHLH)

Answer 15

is a protein structural motif that characterizes a family of transcription factors.

Mutation in certain bHLH can lead to
Waardenburg Syndrome II

Question 16

Lesch-Nyhan Disease

Answer 16

Results from a deficiency in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), causing an excessive buildup of uric acid and de novo purine synthesis due to buildup of PRPP.
Lead to the accumulation in tissues of purines of low solubility.

Question 17

Craniosyntosis

Answer 17

Premature closure of one more sutures in the skull (or other skull suture related effects).
Occurs due to a mutation in the homeodomain protein MSX2. Homeodomain (helix turn helix) is critical for development such as skull in embryo.

Question 18

Androgen insensitivity syndrome (AIS)

Answer 18

AIS includes feminization or undermasculizination at birth,, possible abnormal secondary sexual development at puberty, and infertility. Occurs in males who have mutation with the ligand domain of androgen receptors- A zinc finger DNA domain binding protein.

Remember, effects with estrogen or androgen receptors likely involve Zinc finger protein defects.

Question 19

Waardenburg Syndrome II

Answer 19

Deafness, pigmentation defects of eye, skin, and hair. Genes that encode for development of melanocytes
Mutation of transcription factor MITF gene, which is part of the bLHL (basic loop helix motif) DNA binding proteins.

Question 20

Rubinstein-Taybi Syndrome

Answer 20

Characterized by growth retardation, mental retardation, craniofacial dysmorphism.
Mutation in the CREP binding protein, a transcriptional coactivator for many transcription factors including histone actetlytransferase (HAT enzyme).
The defective activation of histone actetlytransferase will lead to hampered transcription of necessary genes.

Question 21

Leukemia

Answer 21

A hematopoietic malignancy. Generally the result of chromosomal translocation leading to the gain of function fusion proteins- which involves fusion of transcriptional regulators with HATs or HDAC, ultimately effecting activity of transcription regulators

Question 22

Xerdoerma Pigmentosum (XP)

Answer 22

Sun hypersensitive and neoplasm of skin due to Global NER not working/mutated

Question 23

Cockayne Syndrome

Answer 23

Neurological degeneration, impaired development, light sensitivity due due defective Transcription coupled NER

Question 24

Trichothiodystrophy

Answer 24

Is an autosomal recessive inherited disorder characterized by brittle hair and intellectual impairment. Scaly skin.
All photosensitive TTD syndromes have defects in the nucleotide excision repair (NER) pathway
Defective P44 gene

Question 25

Kasugamycin, Strepomycin, Clindamycin, Erythromycin

anything with mycin

Answer 25

Antibiotics that target the ribosome. Can target different processes like peptidyl transferase, initiator tRNA binding, ect.

Question 26

Prion

Answer 26

A prion is an infectious agent, composed entirely of protein, presumed to be the cause of the transmissible spongiform encephalopathies (TSEs). The protein it is composed of, called PrP (short for prion protein) can fold in multiple, structurally distinct ways, at least one of which is transmissible to other prion proteins. It is this form of replication that leads to disease that is similar to viral infection.

Question 27

Composition of the PrPsc (the prion of scrapie)

Answer 27

Predominant secondary structure is Beta-Sheets instead of alpha helix, turn, or coils
Covalent Structure/primary structure is identical between Pr (healthy protein structure) and the PrP-sc (infectious prion)
- yet the Secondary structure is drastically different
-The model of PrP-sc shows that the Beta sheets and other structures is very resistant to proteases

Question 28

PrPSc- Prion protein for Scrapie Summary

Answer 28

The infectious isoform of PrP, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. PrPSc always causes prion disease. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet structure in place of the normal α-helix structure. Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques. It is unclear as to whether these aggregates are the cause of cell damage or are simply a side-effect of the underlying disease process. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber.

Question 29

Alzheimer’s Disease

Answer 29

Plaque buildup from abnormal folding of the amyloid beta proteins and tau proteins
• Plaque’s are toxic, cause inflammation damage
• Tangles from the misfiled tau protein that also is damaging, these tangles are caused by oxidative damage

Question 30

Amyloid Precursor protein (APP)

Answer 30

A normal transmembrane protein that is used in healthy function.
These proteins get broken into smaller pieces by somewhat mysterious ways these defective Amyloid precursor proteins is what leads to the amyloid beta build ups

Question 31

Several enzymatic cleavages can lead to the downfall of the APP (Amyloid Precursor Protein)

Answer 31

The alpha-secretase cut followed by the gamma-secretase cleavage is the 90% of the time pathway more healthy

• This produces a variety of amyloid beta length 32-50 peptides
• Normal Amyloid Beta is not understood physiological

Bace1: Cleavage of APP by the Beta Secretase followed by the Gamma secretase

• Yields Amyloid Beta 40 and 42
• Amyloid Beta 42 is the most disease state related
• Defective Amyloid Beta 40 and 42 are “sticky” and are causing the plaque build up

Question 32

Nonamyloidgenic & Amyloidgenic Pathways in Amyloid Beta creation

Answer 32

Nonamyloidgenic desired pathway with Alpha-secretase and Gamma secretase

Amyloidgenic (Bad) The BACE-1 pathway
- The Beta and Gamma secretase lead to the defffective Amyloid Beta (40 or 42)

Question 33

Apolipoprotein E

Answer 33

Apolipoprotein E= amyloid beta processing and clearance
o The protein has to do with lipid metabolism
-Clears out a variety of lipid molecules
o It will get rid of Amyloid Beta clusters= good to remove plaques
-Overall Apo E2 is the best scavenger very good at clearing Amyloid Beta clumps

ApoE e4 allele a version of the Apolipoprotein E that is NOT GOOD at clearing amyloid beta = increase chance of Alzheimer’s disease
-Roughly 20% of population has! No Bueno

Question 34

Most major causes of Alzheimer’s Disease genetically

Answer 34

o amyloid precursor protein mutations (chromosome 21)
o Presenilin 1 mutations (chromosome 14)
o Presenilin 2 mutations (chromosome 1)

Question 35

BRCA2

Answer 35

Critical gene in suppressing breast cancer tumors
o In mice (and humans?) BRCA2 normally functions in fixing DNA damage that pertains to the breast
o Damaged BRCA2 damage to important checkpoints about synthesis

BRCA2 is normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer.

Question 36

Gleevec

Answer 36

Gleevec inhibits the Kinase of bcr tyrosine, stopping phosphorylating and cell signaling

• a bcr tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML)
• Stops the tumor cell from proliferating

Is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).[1]

Question 37

Angiotensinogen

Answer 37

• Angiotensinogen is a component of the renin-angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance.

-Angiotensinogen is catalytically cleaved by renin to produce angiotensin I in response to lowered blood pressure. Angiotensin converting enzyme (ACE), subsequently removes a dipeptide to produce angiotensin II, the physiologically active peptide, which functions in the regulation of volume and mineral balance of body fluids

Question 38

Cystic fibrosis

Answer 38

• defects in cystic fibrosis transmembrane conductance regulator (CFTR)
• most common mutation is the deletion of F508
• F508 deletion causes protein misfolding

It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.[1] Those with a single working copy are carriers and otherwise mostly normal.[3] CFTR is involved in production of sweat, digestive fluids, and mucus.[4] When CFTR is not functional, secretions which are usually thin instead become thick.[5] The condition is diagnosed by a sweat test and genetic testing.[1] Screening of infants at birth takes place in some areas of the world.[1]