Biomedical Applications of Enzymes and Conjugated Proteins

homeostatic

perturbations of the regulatory machinery responsible for maintaining _______________ balance can be deleterious to health

viral hepatitis, acetaminophen toxicity

can be diagnosed with serum levels of aminotransferases

acute pancreatitis

can be diagnosed with serum levels of amylase and lipase

myocardial infarctions

can be diagnosed with serum levels of aminotransferases and creatine kinases

muscle disorders

can be diagnosed with serum levels of creatine kinase

liver disease

can be diagnosed with serum levels of gamma-glutamyl transferase, lactate dehydrogenase isozyme 5, and alkaline phosphatase

bone disorders

can be diagnosed with serum levels of alkaline phosphatase

conjugated protiens

globular proteins with a prosthetic group.

sickle cell anemia

a genetic disorder that causes abnormal hemoglobin, resulting in some red blood cells assuming an abnormal sickle shape

thalassemia

genetic disorder where the body is unable to produce functioning hemoglobin

transporter

hemoglobin is an oxygen _________________

depot (storage)

myoglobin is an oxygen _________________

iron

the interaction of myoglobin and hemoglobin with oxygen involves _________ in heme

heme

iron surrounded by porphyrin - prosthetic group

porphyrin

organic macromolecule in heme that surrounds iron

conjugated

_________________ double bonds in porphyrin allow for resonance and increased stability due to flow of electrons

cyanide

___________ is toxic because it disrupts the physiological function of the heme protein cytochrome oxidase

carbon monozide

___________ is toxic because it disrupts the physiological function of hemoglobin

myoglobin

apomyoglobin + heme =

myoglobin

present in muscles to hold onto oxygen; globular (axial ratio = 1.8); contains 8 alpha-helices (A through H); 153 amino acids, and has a molecular weight of approximately 17000

hemoglobin

has quaternary structure, composed of four subunits; undergoes conformational change from T to R state when oxygen binds

normal adult

a2B2 = HbA, which is __________________________ hemoglobin

fetal

a2gamma2 = HbF, which is _______________________ hemoglobin

sickle cell

a2B2S = HbS, which is ________________________ hemoglobin

minor adult

a2delta2 = HbA2, which is _______________________ hemoglobin

cooperative binding

process that maximizes the ability of hemoglobin to function as an oxygen carrier, as a molecule of oxygen binds to hemoglobin more readily if other oxygen molecules are already bound. The first oxygen "forms a crack" in hemoglobin, initiating the T to R conformational change

T

taut conformation of hemoglobin when it does not contain oxygen

R

relaxed conformation of hemoglobin when it is loaded with oxygen

carbamate

hemoglobin can carry carbon dioxide as _________________; form salt bridges that stabilize the T state (deoxyhemoglobin)

bohr effect

a decrease in the amount of oxygen associated with hemoglobin and other respiratory compounds in response to a lowered blood pH resulting from an increased concentration of carbon dioxide in the blood.

Bohr effect

hemoglobin can carry protons through the __________________

carbonic anhydrase

enzyme that catalyzes the reaction between carbon dioxide and water to form bicarbonate (and the reverse)

peripheral tissues

in the ___________________, carbon dioxide produced by the citric acid cycle reacts with water to form bicarbonate, which then can deprotonate into carbonic acid. The released proton protonates histidines in hemoglobin

lungs

in the _________________, inhaled oxygen binds to hemoglobin and causes for the deprotonation of histidines. The protons react with carbonic acid which gets converted to bicarbonate. Carbonic anhydrase converts the bicarbonate to water and carbon dioxide, which gets exhaled

1

myoglobin has a p50 of __________, meaning it binds oxygen at a very low pO2 (at this pO2, myoglobin is 50% saturated with oxygen)

26

hemoglobin has a p50 of ________, meaning it is able to release oxygen at higher pO2 (at this pO2, hemoglobin is 50% saturated with oxygen)

glycated hemoglobin

fraction of ___________________________ (HbA1c) si proportionate to normal blood glucose concentration; useful for diagnosis and management of diabetes mellitus and efficacy of treatment within a 3-month window

5

healthy HbA1c levels should be less than _____%

6.5

HbA1c levels that are ______% or higher are indicative of type 2 diabetes mellitus

collagen

the most abundant fibrous protein in the body, in addition to keratin and myosin; provides structural strength for cells (cytoskeleton) and tissues such as bones, teeth, tendons, and ligaments; axial ratio of 200

25

fibrous proteins constitute more than ________% of protein mass in the body

lysyl, valines

blood glucose that enters the erythrocytes non-enzymatically glycates the e-amino groups of ___________ residues and the B-chain of N-terminal ______________ of hemoglobin

elastin

connective tissue fibrous protein with rubber-like properties

elastic fibers

composed of elastin and glycoprotein microfibrils; found in the lungs, walls of large arteries, and elastic ligaments

desmosine cross-link

allows elastin to be stretched several times their normal length but recoil to original shape when force is relaxed; occurs when elastin lysine residues come close together and form a pyrimidine ring

oxidative deamination

process that converts tropoelastin into mature elastin with desmosine cross links

tropoelastin

immature elastin without rubber properties

small, nonpolar

elastin is rich in _______ and _____________ amino acids such as glycine, alanin, valine, as well as proline and lysine

procollagen

larger precursor peptide of collagen; consists of repeating glycine, lysine, and proline residues - alpha helix of 1000 amino acids; triple helix

vitamin C

necessary for the hydroxylation of lysine and proline in collagen synthesis

hydroxylysine

select _____________________ residues are glycosylated with glucose and galactose, catalyzed by glucosyl and galactosyl transferases in the collagen biosynthesis process

tropocollagen

after procollagen is secreted from golgi vacuole into the extracellular matrix, selective proteolysis occurs when peptidases cleave the N- and C-termini, forming ______________________

mature collagen

when certain lysyl residues are oxidized to aldehydes that form covalent bonds with other lysines to cross-link the individual peptides, ________________ is formed

glycoprotein

collagen is a fibrous ____________________

glycosaminoglycans; proteoglycans

chondroitin, keratin, and aggrecan sulfates are specific carbohydrates known as ________________________ attached to proteins to form ______________________

proteoglycans

composed of repeating disaccharide unites of glucosamine and/or galactosamine attached to a core protein branching off a central hyaluronic acid core

glycosaminoglycans

the ______________________ constitutes more than 80% of the weight of the proteoglycan molecule

proteoglycans

act as lubricant and structural components of connective tissue, especially in cartilage. Can also act as shock absorbers

heparan sulfate

glucosamine that regulates a wide range of activities, such as angiogenesis and blood coagulation

musins (mucoproteins)

proteoglycans that are found at

N-acetylgalactosamine

mucins contain about 80% O-glycan chains, usually containing ____________________________

serine, threonine, proline

musins contain repeating amino acid sequences rich in _________, ___________, and ________________ (VNTR). Cysteine is also important.

viscoelasticity

the extended structure of mucins contribute to their high ________________ and resistance to proteolysis

thallasemia

characterized by lower levels of hemoglobin and red blood cells that leads to fatigue, weakness, pale skin, slow growth, abdominal swelling, and dark urine

iron deficiency anemia

characterized by low iron levels that leads to dysfunctional hemoglobin and a number of symptoms as well as headaches, cole extremities, brittle nails, tongue inflammation, and poor/strange appetite

scurvy

characterized by vitamin C deficiency anemia

a1-antitrypsin deficiency

characterized by destruction of lung tissue due to the inability to stop elastase, which is a protease that degrades elastin, leading to trouble breathing, jaundice, and liver cirrhosis

menkes syndrome

characterized by low levels of copper, weak muscles, sparse thin hair, deterioration of growth and mental abilities. Enzyme involved is lysyl oxidase involved in cross-linking of tropocollagen

osteoarthritis

characterized by loss of chondroitin in cartilage tissue that leads to increased bone friction, pain, joint, damage, and movement disability

Ehlers-Danlos syndrome

characterized by overly flexible deformed joints, stretchy/fragile skin, and rupturing blood vessels due to loss of connective tissue. Many more symptoms have been reported

brittle bone disease

osteogenesis imperfecta; characterized by by easily-breaking bones due to mild trauma or lack of any causes

hemoglobin

thalassemias are associated with ____________________ dysfunction

hemoglobin

iron-deficiency anemia is associated with ____________________ dysfunction

collagen

scurvy is associated with ____________________ dysfunction

elastin

a1-antitrypsin deficiency is associated with ____________________ dysfunction

collagen

menkes syndrome is associated with ____________________ dysfunction

chondroitin

osteoarthritis is associated with ____________________ dysfunction

collagen

Ehlers-Danlos syndrome is associated with ____________________ dysfunction

collagen

brittle bone disease is associated with ____________________ dysfunction