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A. Dioxygen carriers for storage and t t ransport
1. hemoglobin and myoglobin
2. hemocyanin
3. hemerythrin
B. Dioxygen Dioxygen reactions reactions in biosynthesis biosynthesis
1. monooxygenases
a. cytochrome P450
b. t i yros nase
c. methane monooxygenase
2. dioxygenases
C. Dioxygen reactions in respiration
1. cytochrome c oxidase oxidase
2. four‐copper oxidases
Monooxygenases
Monooxygenases are enzymes that incorporate one hydroxyl group into substrates in many
met b li th I thi ti th t t f di d d t h d l tabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl
group and one H2O molecule by the concomitant oxidation of NAD(P)H.
Cytochrome P450
CYPs use
a variety of small and large molecules as substrates in enzymatic
reactions.
They are, in general, the terminal oxidase enzymes in electron transfer chains,
broadly categorized as P450-containing systems.
P450: the spectrophotometric peak at the
ab ti i f th (450 bsorption maximum o
f the enzyme (450 nm) h w
hen
it is in the reduced state and complexed with CO.
The absorption spectrum of cytochrome P450-CO complex
CYP enz
ymes have been identified in all domains of life - animals, plants, fun
gi,
The absorption spectrum of cytochrome P450 CO complex
showing the characteristic Soret peak at approximately 450nm
y ,p , g,
protists, bacteria, archaea, and even in viruses. However, the enzymes have not
been found in E. coli. More than 18,000 distinct CYP proteins are known.
More than 18 000 distinct CYP proteins are known Most CYPs require a protein More than 18,000 distinct CYP proteins are known. Most CYPs require
a protein
partner to deliver one or more electrons to reduce the iron (and eventually
molecular oxygen).
Based on the nature of the electron transfer proteins, CYPs can be classified into:
Cytochrome P450
Microsomal P450 systems in which electrons are transferred from NADPH via
cytochrome P450 reductase (variously CPR, POR, or CYPOR). Cytochrome b5
(cyb5) can also contribute reducing power to this system after being reduced by (cyb5) can also contribute reducing power to this system after being reduced by
cytochrome b5 reductase (CYB5R).
Mitochondrial P450 systems, that employ adrenodoxin reductase and adrenodoxin
t t f l t f NADPH t P450 to
trans
fer elec
trons
from NADPH
to P450.
Bacterial P450 systems, that employ a ferredoxin reductase and a ferredoxin to
transfer electrons to P450.
CYB5R/cyb5/P450 systems in which both electrons required by the CYP come from
cytochrome b5.
FMN/Fd/P450 systems originally found in Rhodococcus sp. in which a FMN-domaincontaining
reductase is fused to the CYP.
P450 only systems, which do not require external reducing power. Notable ones
include CYP5 (thromboxane synthase), CYP8 (prostacyclin synthase), and CYP74A
(allene oxide synthase).
Enzyme found mostly in liver
Cytochrome P450
- steroid hormone biosynthesis from cholesterol
- metabolism of xenobiotics-compounds which are not normally found
Cytochrome P450 has a wide range of roles
- metabolism of xenobiotics-compounds which are not normally found
in the body
- Drugs
- Co pou ds ood p oduced by coo g (po ya o a c yd oca bo s, mpounds in food produced by cooking (polyaromatic hydrocarbons,
also in tobacco smoke) or microorganisms
- typically organic molecules which are poorly soluble in water
• Cytochrome P450 aids in the metabolism of xenobiotics by adding OH to
increase the water solubility of the compound.
• The OH added by P450 can then be used to attach sulfate (SO 2- The OH added by P450 can then be used to attach sulfate (SO ) or a sugar 42 ) or a sugar.
• The modified drug can be more readily removed by the kidney.
• Because this enzyme catalyzes the addition of one oxygen atom, it is termed a
monooxygenase.
Grapefruit and drugs a potent mix
Grapefruits are chalk full of vitamin C, potassium and natural fiber. So they have
to be good for you, right? Well, not necessarily.
Taking a swallow of grapefruit juice to down your prescription medication could
play havoc with the digestion of certain drugs, increasing the amount of
medication released into the bloodstream, which could lead to harmful levels
or drug toxicity
To com
p y y jy g g p j licate matters, if
you have alwa
ys enjo
yed a
glass of
gra
pefruit juice,
stopping this habit could cause the opposite effect, your body will absorb too
little medication.
Drugs that interact with grapefruit juice
Anxiety: Xanax Buspar Versed Halcion Xanax, Buspar, Versed, Halcion
Depression: Luvox, Zoloft
Allergies: Allegra
Abnormal heart rhythm: Abnormal heart rhythm: Cordarone quinidine Cordarone, quinidine
Heart disease/stroke/blood clots: Coumadin
Epilepsy: Tegretol
Cancer: C l h h id t id if f id t if i bl ti Cyclop
hosp
hamide, e
toposide, ifos
famide,
tamoxifen, vinblastine,
vincristine
Cough: Dextromethorphan
HIV: A C i i Vi t N i F t Agenerase,
C
rixivan, Viracep
t, Norvir,
For
tovase
Heart disease/High blood pressure: Coreg, Cardizem, Plendil,
Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan
Asthma/Emphysema: Theophylline
High cholesterol: Lipitor, Lescol, Mevacor, Zocor
Pain: Alfenta, Duragesic, Actiq, Sufenta
Role of nitric oxide in human body
• Nitric oxide as a neurotransmitter
• NO is a signaling molecule but not necessarily a neurotransmitter NO is a signaling molecule, but not necessarily a neurotransmitter
• NO signals inhibition of smooth muscle contraction, adaptive relaxation, and
localized vasodilation
• Nitric oxide believed to play a role in long term memory
• Memory mechanism proposed is a retrograde messenger that facilitates Memory mechanism proposed is a retrograde messenger that facilitates
long term potentiation of neurons (memory)
• Synthesis mechanism involving Ca/Calmodulin activates NOS-I
• NO travels from postsynaptic neuron back to presynaptic neuron which
activates guanylyl cyclase, the enzyme that catalyzes cGMP production
• This starts a cycle of nerve action potentials driven by NO
Nitric oxide in circulatory system:
• Released in response to high blood flow rate and signaling molecules.
• Highly localized and effects are brief.
• If NO synthesis is inhibited, blood pressure increases rapidly.
NO aids in gas exchange between hemoglobin and cells
• Hemoglobin is a vasoconstrictor Fe scavenges NO Hemoglobin is a vasoconstrictor, Fe scavenges NO.
• NO is protected by cysteine moiety when O2 binds to hemoglobin.
• During O2 delivery, NO locally dilates blood vessels to aid in gas exchange.
Nitric oxide in Muscular system:
NO signals inhibition of smooth muscle contraction
• Ca(II) is released from the vascular lumen activating NOS
• NO is synthesized from NOS III in vascular endothelial cells
• This causes guanylyl cyclase to produce cGMP
• A rise in cGMP causes Ca(II) pumps to be activated, thus reducing
Ca(II) concentration in the cell
• This causes muscle relaxation