MCP 11L Flashcards
Most oxygen in the body is used for oxidative phosphorylation by the enzyme _______
Cytochrome oxidase
The Km for Cytochrome oxidase is _____
Less than 1 torr
Hemoglobin is a tetrameric protein with the quaternary structure ______
alpha 2 beta 2 heterodimers
The distal heme pocket is where _____ binds
O2
Less than _____ % oxygen as measured by a pulse oximeter is cause for alarm
90%
Myoglobin has a _____ shaped binding curve while hemoglobin has a _____ shaped binding curve
Hyperbolic
Sigmoidal
The p50 for myoglobin is _____ torr while the p50 for Hemoglobin is _____ torr
2.6 torr
26 torr
Hemoglobin in the ____ state oxygen is not bound. In the ___ state favors oxygen binding
T-state
R-state
An effect of something happening at another site on an active site is called _____
Allostery
A type of allostery in which what is happening at one site promotes the same thing to happen at another identical site is called _____
Cooperativity
_____ binds to an allosteric site on hemoglobin in the T state (increasing/decreasing) the O2 affinity and shifting the curve to the right
BPG
Decreasing
A low pH shifts the hemoglobin O2 binding curve to the (right/left)
right
CO2 effects Hb binding by the synergy of both the Bohr effect and by ________ of the N-terminal amino groups of blood proteins
Carbamylation
Fetal Hemoglobin has the subunits
Alpha-2 Gamma-2
_______ is a defect in the production of alpha chains of hemoglobin
Alpha thalasemia
______ is a defect in the production of beta chains and can be either “major” or “minor”
Beta Thalasemia
Name the Wild Type of Hemoglobin
1) Normal Adult (Alpha-2 Beta-2)
2) Adult with Fetal gamma (Alpha-2 Delta-2)
3) Fetal Hemoglobin (Alpha-2 Gamma-2)
1) HbA
2) HbA2
3) HbF
Name the Variant Type of Hemoglobin:
1) Sickle cell (Alpha-2 Beta*-2)
2) Mild Sickle Cell (Alpha-2 Beta x-2)
3) Alpha Thalsemia (Beta-4)
4) Gamma 4
1) HbS
2) HbC
3) HbH (B4)
4) Hb Barts
The two basic building blocks of Heme are _____ and _____
Glycine and Succinyl CoA
Hemoglobin is synthesized by the enzyme ______ to make delta aminolevulinate (ALA)
delta Aminolevulinate synthase (ALAS)
The gamma subunit of HbF bind BPG (more/less) tightly and has a (higher/lower) O2 affinity than the adult Beta subunit of HbA
Less tightly
Higher affinity
The hemoglobin protein of alpha and beta chains WITHOUT the prosthetic Heme group is called
ApoHb
Heme is Fe chelated by _______
Protoporphyrin IX
Hemoglobin in the T state binds O2 with (low/high) affinity
Low
Hemoglobin in the R state binds O2 with (low/high) affinity
High
BPG, CO2 and H+ all (increase/decrease) Hemoglobins O2 binding affinity
Decrease (releases O2)
BPG stabilizes the (T/R) state
BPT stabilizes the T state, decreases O2 affinity
Carbamylation of N-terminal amino groups stabilizes the (R/T) state of hemoglobin
T state (releases O2)
Fetal HbF has a (higher/lower) binding affinity than maternal (HbA)
Higher
Hemoglobin in which the iron in the heme group is in the Fe3+ (ferric) state and unable to carry oxygen
Methemoglobin
A disease with too much methemoglobin is called
Methemoglobinemia
Around the ring of protoporphyrin IX, what are the side chains (list 8)
MVMVMPPM
M=Methyl
V=Vinyl
P=Propionate
Changing the position 2 side group of Heme B makes ______
Heme A
Covalently bonding a cystine residue to Heme B makes ______
Heme C
Glycine and Succinyl CoA are combined to form ______
Gamma-Aminolevulinate
ALA
Two ALA (Gamma-Aminolevulinate) are combined to form ______
Porphobilinogen (PBG)
The Zn cofactor of ALA can be replaced by ______ leading to a failure to form Porphobilinogen
Lead
Four molecules of Porphobilinogen (PBG) combine to form ______, a tetrapeptide
Uroporphyrinogen I
Uroporphyrinogen I is converted to Uroporphyrinogen III and then ________
Protoporphyrin IX
Heme is made in the liver in order to make the enzyme ______
Cytochrome P450
Genetic deficiencies in heme metabolism are called _____
Porphyrias
Name the disease:
Deficiency in uroporphyrinogen III co-synthase.
CEP
Congenital erythropoietic porphyria
Name the disease:
Partial deficiency in ferrochelatase
Accumulation of (soluble) Coproporphyrinogen III
Less severe than CEP
Protoporphyria
Name the disease:
Caused by partial (50%) deficiency of porphobilinogen (PBG) deaminase leading to accumulation of ALA and PBG
AIP
Acute Intermittent Porphyria
Name the disease:
Deficiency in uroporphyrinogen decarboxylase in liver. Leads to photosensitivity. Precipitated by ethanol or contraceptive pill.
PCT
Porphyria Cutanea Tarda
(a porphyria of the skin late in life)
PBG stands for ____
Porphobilinogen
Removal of aging red blood cells occurs in the _____
Spleen
_____ binds methemoglobin dimers for storage
Haptoglobin
_____ binds free heme with higher afinity than any protien for storage to prevent iron loss
Hemopexin
_____ binds free iron in plasma to prevent iron loss
Transferrin
Biliverdin is reduced by NADPH to ______
Biliruben
Biliruben diglucuronide is called _____
Conjugated bilirubed
Massive breakdown of red blood cells resulting in overproduction or free bilirubin. The liver cells cannot conjugate bilirubin at the rate it enters the liver. Hence build up of conjugated bilirubin in blood
Prehepatic jaundice
Disease condition of the liver (eg hepatitis, cirrhosis) that prevents uptake or conjugation or bilirubin
Hepatic jaundice
Blockage of bile flow out of the liver and into the intestinal tract, buildup of conjugated bilirubin
Posthepatic jaundice
Jaundice:
High conjugated bilirubin
(Prehepatic/intrahepatic/posthepatic)
Intrahepatic or posthepatic
Jaundice:
AST or ALT high
(Prehepatic/intrahepatic/posthepatic)
Intrahepatic
Jaundice:
ALP high
(Prehepatic/intrahepatic/posthepatic)
Posthepatic
Jaundice:
Urine bilirubin present
(Prehepatic/intrahepatic/posthepatic)
Intrahepatic or posthepatic
Jaundice:
Urine urobiliruben present
(Prehepatic/intrahepatic/posthepatic)
Prehepatic or intrahepatic
Red blood cells are made in the _____ and degraded in the _____ so iron must be transported back to the marrow
Marrow
Spleen
______ is a glycoprotein synthesized in the liver specialized for iron transport. It lives in blood plasma.
Transferrin
______ is a degraded form of ferritin
Hemosiderin
______, a product of blood degradation, is one of the body’s major antioxidents
biliruben
_____ is a deficiency in UDP-glucuronyl transferase and results in serve jaundice
Crigler-Najjar Syndrome
Neonatal Jaundice can be treated by ________, since the bilirubin breakdown products are more soluble than bilirubin and can be excreted by the liver into bile without conjugation
Phototherapy: irradiation with fluorescent light
Conjugated Biliruben passes from the liver to the _____ the _____ to the intestinal tract
To the bile canaliculi, to the gall bladder, to the intestinal tract
In the intestinal tract, bacteria convert sugary conjugated bilirubin into colorless _____.
Urobilinogens
Urobilinogens made by bacteria in the intestines are oxidized to _______, responsible for the color of feces
Urobilins
The two major iron storing proteins in the body are _____ and it’s degraded form _____
Ferretin
Hemosiderin
The body moves Iron from the Spleen back to the marrow by the iron transporter ______
Transferrin
Absorption of iron is done by the process of ____ ____ endocytosis of iron containing Ferro-transferrin
receptor mediated endocytosis
Ferro-transferin and its receptor are taken in by endocytosis in vesicles called ______pits where the pH is lowered and the iron dissociates
clathrin coated pits
As pH decreases, transferrin tend to (release/sequester) Iron
Release
The alpha globin cluster is on chromosome _____
16
The Beta globin cluster is on chromosome _____
11
The pain associated with sickle cell disease is due to ______
tissue ischemia: blockage of capillaries
The primary cause of polymerization of hemoglobin S is ______, but fever, acidosis and dehydration will all increase the rate of sicking
Deoxygenation
Norm red cells have a diameter of _____ microns and can transverse capillaries as small as _____ microns
7
3
Hemoglobin C and Hemoglobin S are distinct mutations of the 6th amino acid on the (alpha/beta) chain of hemoglobin
Beta
Individuals with sickle cell trait (HgAS) produce more (HgA/HgS)
55-65% HgA
Sickle cell with the genotype SC affect 1/4 of patients and is (milder/more severe) than those with the genotype SS
Milder
For patients with SS painful swelling in the hands and feet in the first 1-2 years of life is called ______ syndrome
Hand-Foot Syndrome
Sickle Cell Disease (increases/decreases) the risk of stroke
Increases
Acute Chest Syndrome is commonly associated with _____
Sickle Cell Disease
Sickle Cell anemia causes enlargement of what organ?
Spleen
Sickle Cell anemia can be treated with the mild chemotherapeutic agent ______ by increasing ______
Hydroxyurea
HbF
The only way to “cure” sickle cell disease is by ______
Bone Marrow Transplant
To determine if a patient affected with sickle cell is a candidate for a bone marrow transplant, you should _______
Test her siblings HLA (Histocompatability Locus Antigens)
A SS patient has O2 sat. 84%. After 2L nasal cannula, O2 is 88% What to do?
Give the patient a transfusion
(single/multiple) amino acid substitutions in the beta globin chain cause sickle cell anemia
single
SS Sickle cell anemia is caused by a single amino acid substitution of glutamic acid to _______
valine
Sickle cells that are permanently locked in the sickle shape are called _____
ICS
Irreversible sickle cells
During a sickle cell event, ischemic cell release a burst of _______ when blood profusion is restored
ROS
Reactive Oxygen Species
Upon repurfusion ________ converts oxygen into superoxide radicals
Xanthine Oxidase
The burst of ROS during reperfusion leads to _______ and _____
Inflammation and
increased expression of adhesion molecules on endothelial cells (bigger plug)
Two transcription factors that modulate the switch from fetal to adult hemoglobin are ______ and _______
HBS1L-MYB
BCL11A
Normal fetal hemoglobin represents _____ to ______ % of adult hemeglobin. Increasing to ______ % could be therapeutic of SS patients.
0.1%
1%
20%
Sickle cell RBCs contain (more/less) O2 radicals than normal blood cells
3X more
In the RBC the most important of non-enzymatic antioxidant is ____
reduced glutathione (GSH)
SS are in double jeopardy because of increased ______ and decreased _______
increased OH- radicals decreased glutathione (GSH)
In RBCs, oxidative stress inhibits ______ and activates ______ which places (-) charged phosphates on the outside where it can associate with Ca2+ and clotting factors
inhibits flippase
activates scramblase
The three membrane proteins responsible for holding a RBC’s shape are ____ ____ and ____
spectrin
actin
protein 4.1
The RBC sickle shape gets locked due to 1)______ and 2) _______ both caused by increased oxidative stress
beta-actin disulfide bridge
diminished alpha spectrin ubiquitination which creates spectrin-actin complexes
Activation of the sickling induced leak channel increases intracellular ______ and decreases _______ and _____
intracellular free Ca2+
decreases K+ and Mg+
The net outflow of ions from and RBC (increase/decreases) osmotic pressure causing _____
decreases osmotic pressure
dehydration
Lowering intracellular GSH leads to increased oxygen radicals and damage to the _____ channels and increased ______ loss
Gardos
K+
______ is a drug that increases intracellular GSH levels, maintaining Gardos Channels and K+ retention
NAC (N-acetylcystine)
Four current treatments for SS disease are 1. 2. 3. 4.
- Antibiotics
- Analgesics
- Hydroxyurea
- Bone marrow transplant
Each hemoglobin has 36 His residues. How many are bonded to Heme?
4
Each subunit has 1 His coordinated to heme
As substrate concentration [S] increases, initial reaction velocity (increases/decreases)
increases
A reaction velocity (v) vs. Substrate Conc. [S] curve is typically shaped like a _______
rectangular hyperbola
Enzymes that follow the typical rectangular hyperbola graph shape can be fitted with the ________ equation
Michaelis-Menten
E + S ES —–> E + P
What rates do we measure?
k1, k2, and k3
(Vmax) * ([S] / ([S] + Km)) = ?
=v
Michaelis-Menten equation
Km = [S] when v = ______ of Vmax
1/2
The catalytic rate of an enzyme is most sensitive to [S] when [S] is («_space;, = , >,»_space;) Km
much less than «
steepest part of hyperbola
fES = v/Vmax
fES = [S] / ([S] + Km)
can calucualte
fraction of total enzyme bound to substrate
Knowing Km allows you to calculate _____ at any given [S]
the fraction of Substrate bound at any given substrate concentration
When does Km approximate Kd?
When K2»_space; K3
Km approximately = Kd when _____
K2»_space; K3
when dissociation of the ES complex is the limiting rate
In M-M kinetics, k3 is also called kcat or the _____ number
turnover
The maximum velocity achievable for a specific concentration of enzyme is called _____
Vmax
Higher kcat /Km implies (more/less) efficiency
More
How quickly the ES complex is used is described by _____
kcat
How much ES complex is available is described by _____
Km
A Lineweaver-burke plot is a ______ plot that linearlizes the Michaelis-Menten equation
double reciprocal
1/v = 1/Vmax + (Km/Vmax)*(1/[S]) is called _____
Linweaver-Burk transformation
These inhibitors compete with the substrate for binding site activity.
Competitive
These inhibitors bind to a site on the enzyme other than the active site
Non-competitive
Ki = [E]*[I] / [EI] is the ____
Disociation constant equation
A higher Ki implies (stronger/weaker) inhibition
weaker
The lineweaver-burk plot with a competitive inhibitor will have the same ____ intercept, but different ____ intercept
same y
different x
Non-competitive inhibitors will have the same ____ intercept, but different ____ intercept
same x
different y
Histamine is a (cytokine/interferon)
cytokine
With _____ inhibition, Km appears to increase in presence of the inhibitor, but Vmax does not change
competitive
With ____ inhibition, Km does not change, but Vmax appears to decrease
Non-competitive
One of the most important amino acids in acid-base catalysis is _______ due to its amphoteric nature
histadine
______ degrades acetylcholine in the synaptic cleft and thus help to control transmission of nerve impulses
AChE
Acetylcholinesterae
Nerve gases such as _____ are irreversible inhibitors of acetylcholinesterase
Sarin
For proteolysis, the RDS is formation of the _______ intermediate due to the energy required to pass though the tetrahedra intermediate
the acyl-intermediate
Most drugs are (reversible/irreversible) inhibitors
reversible
Penicillin is a _____ inhibitor of glycopeptide transpeptidase
suicide
Accumulation of photoreactive uroporphyrinogen I and Coproporphyrinogen I
(Photosensitivity –> werewolf ledgend)
CEP
Congenital Erythropoitic porphyria
The best inhibitors mimic the ______ state conformation of the substrate
transition state
The residues that make the catalytic triad for a serine protease are ______, ______ and _____
aspartate, histadine, serine
The two amino acids used in an aspartyl protease are ____ at the active site
two aspartates
HIV protease is a _____ type protease essential for viral maturation
aspartyl protease
The HIV aspartyl protease is different from the Eukaryotic heterodimer aspartyl protease because it is a smaller, symmetric ______
homodimer
The transition state for peptide cleavage by an aspartyl protease is a ______ type geometry
tetrahedral type geometry
Substrate-based design means that the designed inhibitor will bind the enzyme’s _____ site
active site
Due to the high error rate in reverse transcriptase, ______ is a major issue for HIV therapy
drug resistance
In management of HIV, HAART stands for ____
highly active antiretroviral therapy
The HCV lifecycle includes a _____ protease that is good target for designed drugs
Serine
Positive modulators (allosteric activators) will (increase/decrease) K0.5
decrease
shift sigmoidal curve left
Negative modulators (allosteric inhibitors) will (increase/decrease) K0.5
increase
sift sigmoidal curve right
ATP is allosteric activator for Aspartate transcarbamolyase (ATCase) while _____ is an allosteric inhibitor that increases K0.5
CTP
=Cytidine triphosphate
CTP is an allosteric inhibitor of ATCase that binds at the non-active site to the (low/high) affinity conformation or ATCase
low
ATP is an allosteric activator of ATCase that binds allosterically to the (low/high) affinity conformation or ATCase
high
An enzyme kinase does ______, which activates an enzyme
phosphorylation
An enzyme phosphotase does ______, which inactivates and enzyme
dephosphorylates
Some Enzymes can be switched on and off by phosphorylating and _________ them
dephosphorylating
An inactive precursor form of a protease that can be activated by proteolytic cleavage is called a ______
Zymogen
Activation of trypsinogen to make trypsin is catalyzed by ________ a protease on the surface of the duodenum
enteropeptidase
Many of the enzymes involved in blood clotting are ______ proteases
serine
Factor _____ is the protein missing in hemophiliacs
VIIIa
Vitamin ___ is a co-factor for the enzyme that catalyzes the addition of the γ-carboxyl group to GLA
K
Anti-coagulants such as warfarin or coumadin are competitive inhibitors for vitamin ___
K
Inhibition of Vitamin K by warfarin or coumadin prevents _____ foramtion
GLA
γ-carboxyl glutamate
TPA is often called a ______
clot buster
Plasminogen is converted to plasmin by _____
TPA
tissue plasminogen activator
Fibrin is converted to clot forming peptides by _____
Plasmin
α-1 antitrypsin is an inhibitor of ____
elastase
Elastase is secreted by ______
neutrophiles
Inhibits clotting by binds to the active site of serine proteases
AT III
anti-thrombin
AT III can be stabilized by ______
Heparin
AT III deficiency lead to excessive _____
Clotting (thrombosis)
elastase build up in the the lung with _______ deficiency
α-1 antitrypsin
Too much elastase in the lungs causes ______
emphysema
COPD
PKA is regulated by interaction with _____
cAMP
ALT (or SGOT) can detect _____
viral hepatitis
Amylase can be used to detect ____
acute pancreatitis
Creatine Kinase can be used to detect _____
muscle disorders / MI
Lactase dehydrogenase can be used to detect _____
Liver disease
Lipase can be used to detect _____
Acute pancreatitis
Phosphotase acid can be used to detect ____
carcinoma of prostate
Phosphotase alkaline can be used to detect _____
bone disorderdes, obstructive liver disease
MI can lead to increased plasma ____, ____ and ____
CK-2 (Creatine kinase)
AST (asparate aminotransferase)
LDH-1 (lactate dehydrogenase)
The small group of proteins that inhibit proteases are called _____
serpins
Why do enzyme assays at saturating [substrate]?
Because Δ[S] and Δ[P] will be linear so we can measure Vmax if we know the [enzyme]
two or more enzymes with identical function but different structure are called
isozymes
Acute pancreatitis can be detected by both ____ and ____
amylase and lipase
Heme biosynthesis is regulated at the level of ____ synthesis
ALA
When heme is degraded the toxic gas ____ is produced
CO
Carbon monoxide
The rate limiting step in heme synthesis is the enzyme _____ synthase
delta-Aminolevulinte synthase
delta-ALA
