announcement

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announcement

Hello everyone, this DeepInMed blog 

we are back to the job with one topic or lesson per day though with the same schedule, we admit that we had a rough start but start from today promise you we will do our best. 

tommorrow is the first day 

10 : 30 AM 

thanks for your support 

hello everyone, this DeepInMed blog I am just here today to tell you that I can't upload today's lessons and even yesterday one was missing I really have a situation to solve and then come back hope tomorrow I will be back wish me luck.. really sorry 

pyrimidine metabolism

hello everyone, this DeepInMed blog hope you all doin well. 

So today we are going to talk about pyrimidine metabolism last lesson in the molecular biology chapter, congrats you just made the first step. 

well then pyrimidine synthesis may be similar to purine synthesis since both of them are nucleotides they share sources of atoms which are glutamine, aspartic acid and CO2. 

this the whole process shown in the figure 

the first step is synthesis of carbamoylphosphate from glutamine and the enzyme that catalyze this step is carbamolyphosphate synthetase II (CPS II) in case you were wondering there is carbamoylphosphate I (CPS I)which found in the mitochondria and it's important for urea cycle while our enzyme here works on pyrimidine synthesis here is more details about them 

most important thing to know that is step is rate limiting step for this pathway and carbamoylphosphate synthetase II is inhibited by UMP 

The second step in pyrimidine synthesis is the formation of carbamoylaspartate,

catalyzed by aspartate transcarbamoylase. The

pyrimidine ring is then closed hydrolytically by dihydroorotase. The

resulting dihydroorotate is oxidized to produce orotic acid or orotate and the enzyme that produce it is dihydroorotate dehydrogenase here is a thing you may want to know that is enzyme is the only enzyme in pyrimidine synthesis which is embeded in the inner mitochondrial membrane when all the other enzymes are cytosolic. 

now after we have the orotic acid it's time to make OMP stands for ortidine 5 monophosphate PRPP is again the ribose

5-phosphate donor. The enzyme orotate phosphoribosyltransferase

produces OMP and releases pyrophosphate. OMP, the parent pyrimidine mononucleotide,

is converted to uridine monophosphate (UMP) by orotidylate decarboxylase,

which removes the acidic carboxyl group. 

the other pyrimidines are been synthsized from UMP itself. here is the most high yield things to know about pyrimdine synthesis : 

glutamine → carbamoylphosphate → orotic acid  →  UMP 

diseases that related to this process 

orotic aciduria : this an acutosomal recessive disorder where children born with it defect in UMP synthetase which apparently leads to cut out this process and accumulation of orotic acids and here where is the reason we get the name of orotic aciduria. symptoms orotic acid appear in urine for sure, megaloblastic anemiea (and the reason most patients develop it because B 12 or folate deficincy) and growth retardation. treatment : just give them uridine directly. 

there is another disorder cause accumulation of orotic acids in the urine which is orinthine transcarbamylase deficincy (OTC) which is important enzyme in the urea cycle it combines carbamoylphosphate with orinithine to give citrulline. and when you don't have this enzyme carbamoylphosphate will have no other way but to back to pyrimidine synthesis pathway which will make more orotic acid than the body needs and patients will have the same symptoms of orotic aciduria but don't be confused there is a way to distinguish between them since ONLY in OTC patients will have high levels of ammonia because the urea cycle is dysfuntion while in orotic aciduria it's intact and the baby born with this disorder will have encephalopathy ( lethargy and coma) because of dysfunction urea cycle. 

now back to the pyrimidine synthesis pathway, after we have UMP it convert to UTP by adding to more phosphate from ATP and then converted to CTP and the requries removal of an oxygen group and addition of nitrogen group as shown in the figure below 

there is a chemotherapy agent the mimics the structure of cytidine it called Ara - c (cytarabinose cytosine arabinoside) once it is inside the body it converted to areCTP which mimics dCTP and inhibit DNA polymerase.

now with been said lets move to thymdine synthesis and since this one is only used in DNA that means it only required as nucleotide as deoxythymdine and it is synthesis from dUTP just by adding one carbon molecule and this process consist of three steps 

thymdien synthesis :

step one : UMP → dUDP  enzyme catalyze this step is ribonucleotide reductase 

drugs related to this step : hydroxyurea 

this one inhibit ribonucleotide reductase so it will certainly block formation of deoxyribonucleotides but RNA stay intact, rarely used for malignancy and most common use for polycythemia vera and thrombocytosis, use in sickle cell anemia and causes increase fetal hemoglobin levels (mechanism unknow yet)

step 2 : dUDP  →  dUMP 

step 3 : dUMP  →  dTMP 

and this step is catalyzed by thymidlate synthase. 

purine metabolism

purine synthesis consist of : HMP shunt, amino acids and carbons (tetrahydrofolate and co2).

first step of purine metabolism is to create PRPP which stand for 5 phosphoribosyl 1 pyrophosphate 

from ribose 5 phosphate.

the second step is : glutamine + PRPP → phosphoribosylamide 

the amide group is replaced from glutamine to PRPP 

the enzyme catalyze this step is glutamine :phosphoribosylamidotransferase GPTA which is rate limiting step for purine synthesis this enzyme is inhibited by final products of purines pathway AMP GMP the rate of this reaction is also controlled by intracellular concentration of PRPP because its concentration is normally below michaelis constant or km therefore any small change in the PRPP concentration causes proportional change in the rate of reaction. 

next step is to create IMP whose base is hypzanthine and it is the parent nucleotide for AMP and GMP it's found in tRNA. 

drugs that related to this step: ribavirin (antiviral) 

inhibit IMP dehydrogenase which means it cut the metabolism way and prevent conversion of IMP to GMP as a result all the purines are inhibited. 

mycophenolate : is a ammunosuppressant also inhibit IMP dehydrogenase. 

ribonucleotides are synthezied first then converted to deoxyribonucleotides by an enzyme called ribonucleotide reductase which is composed of two nonidentical subunits R1 and R2, the immediate donors of the hydrogen atoms needed for the reduction of the 2 hydroxyl group are two sulfhydryl (sh) group on the enzyme R1 unit. 

purine salvage : means converting purines from diet or result from normal turn over back into nucleoside triphosphate. 

this requires PRPP because it looks like a nucleotide but without a base and three phosphate so if you put your base and took the phosphate you will have a new nucleotide, the enzyme that catalyze this step for hypoxanthine and guanine is called HGPRT stand for hypoxanthine - guanine phosphoribosyltransferase. but for the adenine has its own enzyme which called APRT. 

drugs related to purine salvage : 6 mercatoprine  6MP: which is chemotherapy agent mimics hypoxanthine and guanine so the HGPRT will think it is them and combine to them and result in structure called thioinosonic acid which is obvisouly cut the salvage way and inhibit multiple steps in de novo synthesis result in decrease amount of IMP GMP AMP. 

Azathioprine : this one is immunosuppressant and converted inside the body to 6MP.

purines breakdown: hypoxanthine and guanine to uric acid as final product as shown in the figure below 

while adenine breakdown is just little more complicated as shown in the figure 

SCID stand for severe compined immuno deficiency syndrome which adenosine deaminase dificiency... well not our concern right now 

diseases related to purine breakdown : Gout : excess uric acid in blood which may look like hyperuricemia as either of them result in excess uric acid in blood the hyperuricemia can lead to deposition of monosodium urate crystals in joints, symptoms are pain, swelling and redness in joints usually result from overproduction or underexcretion or just a lot consumption of purine rich food after a big meal, the definite diagnosis of Gout which can tell you is hyperuricemia or Gout is examination of synovial fluid from an affected joint using polarized light microscope to confirm the presence of needle shaped MSU crystals. remember Hyperuricemia is not sufficent to cause Gout but gout is always preceds with hyperuricemia. 

treatment : acut attacks of gout are treated with Colchicine, prednisone and indomethacin. notice that these drugs prevent formation of microtubules thereby decrease the movements of neutrophils in affected joint and has no effect at uric acid levels, while long term theraputic stratiges involve lowering the level of uric acid below its saturation point these drugs are Probenecide or sulfinpyrazone, that increase renal excretion of uric acid. And allopurinol is used for overproducers because it inhibit xanthine oxidase. 

gout patients may look like this 

but you must be careful when you describe allopurinol because 6 MP and azathioprine and metabolized by xanthine oxidase too so when you describe allopurinol allong with them this will boost their effect and it may be toxic but sometimes you may need to boost their effect on purpose. 

lesh-Nyhan syndrome :   this rare X linked recessive disorer associated with complete absence for HGPRT  which cut the salvage pathway for sure and the lack of this pathway causes increased PRPP levels and decreased IMP and GMP levls as result GPAT has excess substrate and decreased inhibitors then the de novo purine synthesis is incresed and without salvage it is all going to turin into uric acid which cause hypernuricemia. the child will have self mutilation (bitting or scratching) hypotonia, chorea and there is no treatment sadlly. 

reference I used is lippincot and some online lectures 

this is my first day please drop your opinons down the comments and how good or even bad you think I was ? 😂 and thanks 

introduction to metabolism

hello everyone this DeepInMed blog, well I know this wansn't on the schedule but must do. 

definition of metabolism : meta : changes 

ism : in the living tissues 

which makes it the chemical changes which happens in the living tissues and study of their nature. 

it doesn't occur Spontaneously but catalyzed by enzymes. 

metabolism if divided into two sections : first one is anabolic or anabolim or synthetic. 

this one turns small molecules into large molecules and consume ATP, energy and heat (endothermic)

the second one is : catabolic or catabolism or degenerative : this one break down large molecules into small ones, ATP and heat are been produced (exothermic). 

DNA structure

hello everyone, this DeepInMed blog hope u all doing well. 

DNA is consider as the genetic unit which contain our genetic code found in the nucleas of eukaryotic cells and cytoplasm of prokaryotic cells.

 

it consist of two strands which contain :

sugar (ribose backbone)         nitrgenous base               phosphate group 

nitrogenous bases are nucleotides so what are they? well basically whole DNA is a polymer and every polymer contain monomers these nucleotides are our monomer they consist of pentose sugar, phosphate group and nitrogenous base, there are ribonucleotides and deoxyribonucleotides the only difference between them is the OH group 

and we also have nucleoside which contain nitrogen base and sugar with no phosphate group attached 

nucleotides are divided into to sections : purines and pyrimidines as shown in the figure  and it is good to know that all nucleotides are synthesized as monophosphate and then converted to triphosphate because triphosphate form is the form which DNA and RNA needs. 

DNA methylation : it is known as adding methyl group to cytosine occurs in segments with CG patters in both strands when DNA is methylated its transcription becomes inactivated in fact more than 70% of human genes are methylated as example you and your brother may share the same genes but it is active on you and not on him that doesn't mean he doesn't have your genes since you have the same parents and if the body found a lot of unmethylated CG strands wandering around that can stimulate and immune response because the body will think it came from bacterial DNA methylation and so what is this ? adding methyl group to cytosine and adenine to bacterial DNA but this one have the opposite effect since it protect bacteria from viruses the mechanism is when a viruse insert its DNA into the bacteria the bacteria will recognize that this DNA is not methylated and destroy it by enzyme called endonucleaseas. 

DNA is so large to fit inside the nucleas so it is packaged in chromatin and chromosomes. chromatins are mainly DNA plus proteins and its condensed into chromosomes as shown in the figure. 

   

one of the most important proteins found inside chromatins are the histones and when they combine with DNA they give us nucleosomes as show in the figure down, histones since it is proteins it consist of peptides there names : H1 H2A H2B H3 H4 

and contain amino acids specially ariginine and lysine which are positively charged so the can bind strongly with the negatively charged phosphate backbone 

H1 histone is different from the other histones first it doesn't found in the nucleosome core, larger, important for tying together the beads on the string as shown in the figure it is the big large on and these balls are the other histones in the nucleosome cores 

 a clincal correlation related to histones is drug induced lupus 

as the name stand for it happen after taking certain drugs some symptoms like fever, joint pain and rash these patients will develop anti histone- anti bodies in contrast with patients who have classic lupus (similar symptoms) will develop anti double strand DNA anti bodies. drugs that can stimulate drug induced lupus : procainamide, hydralazine, Isoniazid.

chromatin types : heterochromatin : condensed, gene sequences can't transcribe and the reason is significant DNA methylation. 

euchromain :  less condensed, can perform transcribe perfectly and the reason is significant DNA accetylation. 

DNA accetylation : is adding acetyl group to lysine with will relaxe the chromatin and make more prepare for transcription. and there deacetylase which has just the revert effect and the opposite mechanism. 

huntington's disease is one of the diseases which histone deacetyltion may play a roll, where there is abnormal huntington protien and of the possible mechanism by which this huntington protein becomes over active is by histone deacetylation silence the genes which should control the huntington protein. 

this concludes DNA structure.