18-9

KNOW the amino acids three code and one letter code.

u r given the equations.

TWO review articles are going to be on the exam =

know the topics that we dont get to dicuss during the lecture. study the entier paper.

similar ot hte first exam =

diabetes it is one of hte most ocmmon diseases in the countr it is a metabolic diseases. its uauly ggrouped into type 1 and type 2. type 1 is about ten percetn and tyep 2 is 90%. insulin is the hormon mocluel that regualtes ur blood glucose levle. in typ1 is anautiimuen system ur immune system is going to msitakely recognzie ur pancreatic celsl as eneyme. and destroyes the pancreatic beta clels that nroamll produce insulin for us. iinsulime si simple not produced or produced at very lwo lelevs. and ur body can no longer adequetly control the blood glucose levle.

bc ur own imune clel are destrouing ur own pancreatic cells. these patients repsone to insulin tehrpay . we can use isnulein. chepaly using recombinat Dna tech. patients jsut inject insuin once a day and that works. before reomcbina dna tech teh isnsulin had to be purified out of pig pancreas and wasnt safe or cheap. tyep 2 is different. a patients produce insulne but ist ineffective. type 2 ahas a correlation with obseity.

Insulin its a hormine a peptide hormone. two hormoens are importnat for regulating nsulin level there is insulin and glucagon. both are peptide homrones. the effect of insulin is decreasing the blood glucose level because it sitmualtes cells to absorb or intake insulin from the blood into the cell. thus lowering the glucose coneotrion in blood. glucagon has the opposite effect. it increase the blood glucose ellve.

how u would ur boyd icnrease the blood glucose lelve. so insuline decasees by abobring glucose that comes form ur meal. ur blood glucsoe level goes up aftera. mea. but then ur body recongizes it and secretes insulin and then cells from that isngla abobr insulin and lowers the levle. but how does u body increase the glycose elvle? it will breadk down glycoen, plants have starch and we have glycocen in the liver. glycogen is a polymer of glucose so when we have excess glucose ur body will make glycogen and keep it in the levle. and when blood sugar lelve is too low it will break down glycogen . so insulin glucan have opp effects.

ADIposcyte are fat storing cells. so.u. eat a male glucose levles go up and insulin is released so these cells ahve insulin recpeto rpotien on the surface. that has abinding site ofr insulin . these insulin receptosr are tyrosine kianses. iso tyrosin kinases pshorylates the subsutrate usually a protein on the tyrosin residue. it catalyzes the transfer of a phsophate group from a ATP to a tyrosine R group of that substrate mocleule. the insulien. receptor is unique in that it autophohoylates. so the subustrate protein for that kianse is itself. when it receives the isnulin singal it will active the enzyme activity and phohoylate it self. and the the phosylated from of hte enzyme phorlyaes another protien called IRS. that activates IRS and starts a cascade of singling reactions. this results in displaying many copesi of a protien called GLUT4 whichi s a glucose uptake transport type4 one the cell surcae. the anme impales this si a tranporter protein for gluycsoe. glysoe is a large hydrophilic moclule it cant simply diffuse into the cell throuhg the lipid bilayer. . it needs tranporter proteints and uhave manu. GLUT4 is just one of them. s since this i s an adipoctye once the glucose gets into the cell tehres a metabolic pathways that will produce glycerol.

By tranofrming the tglucsoe mcolule, glycerol is a comepotneo fo fatty acids. adipcoytes will use glycerol that is jsut made using glucose and thene steifiy it with fatty acids and make fat moclules. whihc also we calle triglyceride . so then its goignt o store that fat moclule inside the cell until ur body needs it and u can see what might happen if ur body doesnt produce enough insuling or ud isnulin receptor no longer repsonds to insulin.

as in case f tyep 2 diabiets its not going to intake glucsoe ofrm the blood so glucsoe levle in blood is high. high lgucose level is dangerous. bc these sugars like the reuding sugars are chemicaly reactive and it willr eact with proteins. one of the first proients to get glucated by glucose is hemoglobin. so ur equialnetly modifying ehmogrlboibnnstructure. by attaching a glucsoe meolcuel to its. and ur heomglboin is not as affect . ant hat causes problems. one intersting points i sthat ur body has to repsond immeditly to incrasing lgucsoe levls. bc as soon. as u eat ur lunch breakfast dinner ur lgucose levgsl will spike and that means there snot enought ime to make these GLUT4 tranporter enzyme trhouhg the normal pcoess of dna trnaciption mRNA trnatlion. that takes too long. suusaly how it works is that these adipocytes have a viescle. and the mermabre of thsi vesicle already contain the GLUt4 trnaporters and what hte insulin is doing is activiting this isngling pathway whose ultimate effect is to move these veiscles onto the cell sruface

thereby displaying the premade glut4 tnraportner on the clel sruface. so the celluarl repsonie is rapid if u had to start form trnaltion it would take too long.

cadiovacular idsease -

nnumber one killer . there is a lcose relationship with cardiovasualr disease and lipids. the mcojluela basisi of these cardiovascualr disease is not fully understood. tehrs is a cleawr colleriaton between lipid level in urboyd and cadiovasucalr disease.

choelstrol is a type of lipid molcule. esterified form of choelstrol is how ur body stores choelstrol. triacylgerlcerols i th as a glycerol bakcbone and each of the hydroxyl groups can be esterified to a fatty acid molcule. at the botom two fatty acids are shonw. this is a fully saturated fatty acid found in plants.

animla fat andher eis an unstatured fatty acid that we find in plants. all thes emocluels are hydrophbic. it does not dissolve easily in water that menas that id does not dissolve well in blood. bc ur blood is mostly water. these its still lipids mocluiesl need to be traported withing ur body. choelstrol can be obtained directly from diet and ur boyd can syntrehsize it this is hwy jsut removing choelstrol form ur diet does tn solvge all the probelms. bc ur boyd syntehsizes it even if u stop eating. one of hte eyzmes in choelstrol biosyntehisi z is HMG coa reducstat. e Statins are cholestrol lowering binding drugs and are inihibotrs invioled in makig choesltorl. if u inhibit this enzyme ur body will produce less choelstorl and that will lead to lower choelstrol levels in the blood.

there are many types of cardiovasc disease. atheroscleoris which si ahrdening of hte artiesi. it happens over decases its a low process. healthly bloo vells on the right is atherosclerosis. so atheroscleoris i has. ariaded path which is called plague that happens in the arterial wall. this mateiral is very rich in fat choelstorl and calcium. it narrows the artery that means whiever tissue is ebign served by that artery its not going to receive suffiecent o2 and that. leads to many problems. the plague can also retupture and the facgemtns can also bloikc arties and that is a problme. is something like that happens in ur cardia artiesi that will lead to heart attack.

lipids are oil solubale thye are not water soluble yet they still have tobe transported form one lcoaiton to another inside ur boyud. so lipids are tranpsoted in blood as protein lipidc complexs called lipoproteins. heomlgobini s o2 carrier and these protiens are lipid carries. tehre are dif types of kipoproitnes that vary in size and lpid compositons. and also the type of protiens they contain.

so these u probaly heard of VLDL LDL andHDL. very low densith lipoprotein low densith and high density liporopteisn

LDL is what we called the bad choelstr HDl is the good. they are liporptoeins which are choelstrol carrying proitnes. tehse liporporients esiclaly. the protien compeonto f liporoitens are reconzed by receptors on cell sruface. so various cells they will lbidn o thtese liporoeitns and take them insdie to the cell and use the lipids, the fatty acids and choesltrol mcoluesl like membrane syntehsize.

athrescoelsis if there is adamgen in ur blood vessel, teh LDL will infiltrate into the neraby tissue. so LDL will rperesent by that yellow sphere. and again ur immune system , bc its doing its job, it recognizes thsi as a problem and ur macrphages iwll come and engluf this. but in this process it realses v arious cytokines. and it stimulates muscle cells profliferiotn in that region and those muscl cells will migrate towards the blood vellse and that is whats causing these plagues. so. u ahve a concentrion of macrophage that contaons a lot of LDL proitens which are fully of fatty acids and cholestrol and as well as this muscle tissue so contriing the blood vessle and sometiems even rupturing.

anothe rbig one is cancer. this is due to unregualted clel grwoht. oaky so essientaly any tissue if the cell growth is unregualted the cells will invade the surroudnign tissue and we end up witha begning tumor sometiems also they will detach form the tissue and spread to otehr part so of the body whihc we call malignant tumor. and that process we call metassit more than 200 di types of cancner have been domcuemtn. so 200 okay and these are cancers associated with overweight abd obseity . diabets types 2 is associated iwth overweight cancer obesity.

so cancer is a mutlfcatoiral disease. gentic as well as envieometnal factors. some whihc are lsited and explaisn. for a long time now that many of these cancer cells overexpress a proiten called EGF receptor. EGF is epdiemral growth factor . so egf receptors is a proetin that iwll bind that hromone and start a singling cascade. and usualy it works its dorman its not acative as soon as it receives the singal so the EGF moclule, bidni ght eegf mocluel causet he gf recpe3tor to dimerize usualy its in the monomeric form. when it dimerizes its activated.

So this

EGF receptor is a dimeric protein, okay? And usually

the way it works is it's dormant. It's not active

normally, okay? But as soon as it receives the signal,

okay, the EGF molecule, binding of the EGF molecule

causes the EGF receptor to dimerize, okay? Usually

it's in this monomeric form, okay? But when it

dimerizes, it is activated, okay? It's also a tyrosine kinase,

okay? It phosphorylates specific tyrosine residues.

OK. And that activates, that initiates a signaling

cascade involving all these different

proteins. OK. The ultimate protein that gets activated

is a transcription factor. These are proteins that

affect gene expression. OK. And the particular

transcription factors that this pathway activates

are the ones that activate genes associated with cell

growth and proliferation. So, if this pathway is

overstimulated, that will lead to abnormal cell

growth and proliferation. So, like I said, a lot of

cancer cells overexpress the EGF receptor proteins

on the cell surface. Why is this such a big

problem? okay and this is a natural question

because it should not be a problem as long as there

is also a no similar increase in the EGF level

right unfortunately it is still a problem because

if the concentration of the EGF receptor monomers

increase okay it will dimerize even in the

absence of the EGF signal. Just because there are

many, many copies of this on the cell surface,

it doesn't require EGF to dimerize.

It'll dimerize in the absence of EGF. That

means this pathway gets turned on even if there

is no EGF signaling. And this is a very common feature of many cancers. All right. Okay, now let's move

to infectious disease. Okay, cholera is one of

them. This is caused by this pathogen, Vibrio

cholerae. It's a bacterium. Okay, this is usually not

a big problem in developed countries because we have

clean drinking water, right? But it's a big problem

in developing countries that lack clean drinking

water. So once this bacterium invades your

body, it'll release toxins. These are protein

toxins called exotoxin. It has two parts. It has

A subunit and B subunit. It's a complex, AB

complex. Your cells have a receptor, unfortunately,

a receptor that binds this toxin, and this toxin

will get pulled into the cell, where the A and B

subunits now dissociate. So the function of the

B subunit is simply to bind to the receptor,

to allow the toxin to get in. But once

inside, they dissociate. And from there on, it's the A subunit that does

all the bad things. What does the A subunit do? It interacts with a specific

GPCR protein. We talked about GPCRs in the last

lecture. These are signaling proteins involved in

many different pathways, and usually GPCRs are

only activated when it receives a signal from the

outside, when a hormone binds to the extracellular

side of the GPCR. So it activates the GPCR,

and also because it's a GTPase enzyme, eventually

it turns itself off. You don't want signaling

to continue indefinitely. So your body has evolved

ways to deactivate it after a certain period of

time. But what this toxin does is it binds to the

GPCR, particularly to the G protein, and it

activates it permanently. So again, now this GPCR pathway

doesn't require an external signal

to be activated. It's permanently turned

on from the inside, if you will. And the GPCR that's

affected is related to controlling the expression

level of these two transporter proteins, cell membrane

transporter proteins, such that if it's constitutively

turned on, you'll have too much chloride ions being

exported from the cell. and too much sodium ions

coming into the cell. And ion concentrations

are highly regulated. It's very important for your

cells to main a particular ion concentration gradient

across the cell membrane. But by dysregulating

this process, the cell gets into trouble, and you're not going to feel well. Another big one, AIDS, okay, this is also an

infectious disease, it's caused by, not by a bacterium,

but a virus called the HIV virus, okay, or human

immunodeficiency virus, okay. HIV is a retrovirus,

okay? It means that its genome exists in the form

of RNA, okay? And it has to be reverse transcribed

into DNA, okay, before it causes all the havoc,

okay? But the first step in the disease cycle are

these viral particles getting into the cells, into

your immune cells, okay? So these viruses specifically

target your white blood cells, which are

important players in your immune system, particularly

CD4-plus helper T cells. These are named so because

they have a protein called CD4 on the cell

surface, and HIV have receptors for these proteins. So

it can latch on to that CD4 protein, okay? However,

that's not sufficient. It also has to bind to

a second protein called CCR5, which stands for

chymokine receptor type 5, okay? So when the virus

binds to both of those proteins, then it gains

entry into your cells, okay? And it's able to release

its RNA, do the reverse transcription, do the

viral protein synthesis, and create many, many more

copies of itself, okay? We have many effective AIDS

drugs now, okay? We talked about one example a couple

of lectures ago, okay? Okay, and there are

also antibody-based AIDS drugs that bind to these

proteins, CD4 and CCR5, okay, and you can see

how that would prevent the virus from binding,

okay, because an antibody is bound to CCR5

or CD4, okay, that gives less chance for HIV

virus to lack on. Okay. This panel B is very

interesting. Okay. Some individuals have a

mutation in their CCR5 gene. So instead of

expressing the native CCR5, they express a variant

called CCR5 delta 32. Okay. And this mutation

causes this protein to stay inside the cell and not

get displaced, displayed on the cell surface okay and

like I said the virus requires binding to both CD4 and

CCR5 to gain entry but if it if the cell doesn't have

CCR5 on the cell surface it it'll it'll it'll it'll

latch on to CD4 but it's not going to gain entry

okay so there are actually some individuals, okay,

that have been documented that are homozygous for

CCR5 delta 32, okay? This means that person,

both the mom and the dad, have this mutation

of this particular gene, so it doesn't, that person

doesn't express any native CCR5, and they're actually

immune to AIDS. Okay, then next we're going

to talk about some nutrition deficiency

diseases, okay.

So vitamins are critical

to our diet. We have to make sure that we

maintain a balanced diet so we absorb all these

important molecules, okay, and various metals

and ions as well, okay. So let's talk about

the first one, phenylketonuria,

or PKU for short. This has to do with

having insufficient amount of tyrosine

in your body. Tyrosine is one of the 20

common amino acids. So of course you need it to

synthesize new proteins. right but that's not a tyrosine is

also used to as a starting material to synthesize

other molecules such as melanin this is a pigment

molecule found in your skin cells so not enough melanin

increases the risk of skin cancer okay it's tyrosine

is also a starting molecule for synthesizing dopamine

okay a neurotransmitter molecule. So, tyrosine is

very, very important, okay? Of course, we get

tyrosine from the protein that we eat, okay?

But another way that your body accesses

tyrosine is to convert phenylalanine to

tyrosine, okay? There's an enzyme that does this.

It's called phenylalanine hydroxylase, okay? The

name perfectly tells you what the enzyme does. It

puts a hydroxyl group on phenylalanine and converts

it to tyrosine, okay? Individuals affected with PKU have mutations in this enzyme, okay? So that this conversion

is done at a very low level or it doesn't take

place, and therefore, unless you take in sufficient amount

of tyrosine-rich protein, your body cannot produce

these two very important molecules, and that

leads to the disease, okay? Let's talk

about vitamin D, okay? So vitamin D is not

a single molecule, okay? It's a family

of molecules, and the two most

important ones are shown here. This is vitamin

D2 and vitamin D3. As you can see

from the structure, this is going to be

very, very hydrophobic. It's not going to

be water-soluble because these are

all hydrocarbons, and these are hormones.

They are signaling What's interesting

about these two is that because it's relatively

small and also hydrophobic and it's a signaling

molecule, you don't need a receptor for this

on the cell surface. It can diffuse into the

cell directly without transporter proteins. It

can diffuse across the lipid bilayer directly,

and it can even diffuse through the nuclear membrane

as well, because it's highly hydrophobic,

and it acts directly on transcription factors

that's in the nucleus. Okay, so hydrophilic signaling

molecule hormones, since they can't enter the

cell, they have to go through receptor proteins

like GPCRs, okay, and EGF receptors that we

talked about today, but lipophilic hormones can

act more directly. Okay. It turns on proteins that's

involved in phosphate and calcium uptake. Okay.

So vitamin D deficiency results in defects in

bone mineralization. Okay. Calcium is very

important for making your bones healthy, making it

strong. Okay. Your bones strong. So if you don't

have enough vitamin, okay, that leads to rickets in

children or osteoporosis in older adults,

okay? Osteoporosis is, people with osteoporosis

have very brittle bones, okay? So if you fall or even

just run into something, you're likely to break

your bone, okay? But let's talk about another

vitamin, vitamin K, okay? Again, it's a family

of molecules. The structures of vitamin K1

and K2 are shown here, okay? Again, it's a relatively

hydrophobic molecule, okay? So this time, this

is not a hormone, okay, but it's an enzyme cofactor,

okay? Remember, when we talked about enzymes, some

enzymes are made entirely of the 20 amino acids, whereas

other enzymes require an additional factor, okay?

Like a coenzyme or a cofactor that's needed, okay, to

do the chemical reaction, okay? So vitamin K, some

enzymes require vitamin K as a cofactor at

the active site, okay? One of those enzymes

is this beta-glutamyl carboxylase, okay? And

this happens to be an enzyme that's very

important in blood clotting, okay? So when you have

a small injury, most of us, we stop bleeding

after a while, right? Otherwise, we will

die from blood loss, okay? So blood clotting

is very important. For that process to

work, you need this enzyme to be highly

active. For that enzyme to be highly active,

you need that vitamin K cofactor bound at the

active site, right? So vitamin K deficiency

leads to impaired blood clotting, okay, and

increased risk of bleeding, okay? So these

individuals have very difficulty and stop bleeding

once it starts, okay? okay that's it i'll

see you on friday