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| 7782754429 | Sources and Uses of AA | Source: Body Protein: 22g/d Dietary Protein: 70-100 g/d Digestive Enzymes: 70-100 g/d Uses: Feces: 10 g/d Protein synthesis: 300-400 g/d degradation for energy of to make glucose *only significant source of nitrogen in our diet is through protein 3/4 AA come from our own body break down and 1/4 comes from diet | 0 | |
| 7782788020 | Dietary Protein Digestion | Activated duodenum: trypsin, chymotrypsin, elastase and carboxypeptidase and enteropeptidase Stomach: gastrin triggered by food promotes the release of acid and pepsinogen/pepsin autoactivated at PH <2 Pancreas: secretes zymogens and bicarbonate *enzymes in intestinal lumen and villi produce mostly amino acids partially digested proteins trigger the release of secretin and CCK to cause the gall bladder and pancreas to secrete. | 1 | |
| 7782820362 | Regulation of Digestion in Small Intestines | 1. Acid Chyme passes to duodenum- bicarb is release 2. Mucosal cells of pancreas release of secretin and CCK into the blood 3. Gall bladder contracts and pancreas releases juices of inactive proteases (bicarb and zymogens that are cleaved by enteropeptidases that are released in response to CCK) | 2 | |
| 7786082310 | Trypsin | -key for the production of protein digestive enzymes Enteropeptidase first cleaves a minor portion of trypsinogen to trypsin and then trypsin is able to cleave trypsinogen because at its cleavage site is a chain containing lysine ad 4 asp (positive AA chains are its recognition/ cleavage site) Trypsin also cleaves: chymotrypsinogen, proelastase (produces short peptides) and procarboxypeptidase (produces AAs, amino- and di- peptidases also produce) *The digestive enzymes are being degraded and contribute about 70 g of AAs a day, about the same amount of the digestive enzymes being synthesized | 3 | |
| 7786114083 | Pancreatitis | caused by a loss in the trypsin inhibitor causing trypsin to digest molecules in the pancreatic cells (overreactive trypsin) non-hereditatry: duct blockage results in bile back up and tissue damage (>200,000 hospital visits annually) hereditary: mutation in trypsin interaction with its inhibitor (1: 200000) symptomology: pain centered in the upper middle or upper left part of the abdomen, often temporay | 4 | |
| 7786165613 | AA transport | uptake into and out of the intestinal cells occurs through 7 different transporters -large AA's taken in through Na linked transporers (Na/K pumps that use ATP are used to keep the Na concentration in the cell low) -the A-system is used for alanine and small AAs - removed from the cell using AA facilitated transporters and ONLY AAs can enter into the hepatic portal vein *** fetus an neonates can absorb intact protein by pinocytosis (maternal antibodies) ** Absorbed proteins -dipeptides with proline -unusual AAs (beta alanine) | 5 | |
| 7786197948 | Cystinuria | carrier rate 1:50 (1:150) disease 1:7000 (1:10,000) Normally, a kidney cuboidal cell re-absorbs AAs from the glomerular filtrate for export back into the blood at efficiency of 100%, people with this disease have reabsorption of 0.4%. This results in high levels of cystine(from cysteine that was oxidized in the urine) in the urine because it is not absorbed and oxidized to cysteine. Because cystine has limited solubility, stones in the lumen of the proximal tubule form Also high levels of: LYSINE, arginine, orinthine and citrulline because they use the same transporter | 6 | |
| 7786422828 | Pellegra (niacin B3) deficiency | tryptophan can be used to make niacin used in NAD/NADP - dietary loss of tryptophan, causes its victims to experience dermatitis, diarrhea, dementia, and death | 7 | |
| 7786468324 | Hartnup disease | a single defective transporter in epithelial cells (intestine and kidney) abnormal excretion of tryptophan and neutral AAs into the urine and deficient in absorption in the intestine -characterized by intermittent attaches of dermatitis, diarrhea and dementia * affects occur in the brain and skin -have the same transporter int he kidney so what little tryptophan is in the blood gets lost in the urine * mutation is in the SLC6A19 gene that codes for a neutral amino acid transporter | 8 | |
| 7786530760 | Sources of AA degradation | 1. Lysosomal System for extracellular protein ( bacteria, ApoB100- LDL, apoptotic fragments) 2. Digestive enzyme turnover 3. Ubiquitin/proteasome pathway is the major pathway for degradation of intracellular proteins (muscle) | 9 | |
| 7786567553 | Protein Degradation Rates | -Lactate DH: 171 hours - Delta ALAS: 1 hour -HMG-CoA reductase: 0.5 hours -Histone: 2800 hours proteins that are especially short term are involved in the cell cycle | 10 | |
| 7786768848 | Ubiquitin Pathway | 1. Ubiquitin is activated by by an ATP by the E1 complex. 2. E1 complex transfers the ubiquitin to E2 which binds to E3 and adds to the ubiquitin to the target protein 3. Ubiquitin is added to the N terminus and the protein is directed to a proteasome 4. Ubiquitin is recycled by the deubiquitinase(DUB) enzyme 5. The protein is degraded to peptides and is either added to an MHC complex or is degraded further by the abundant aminopeptidases inside the cell to amino acids | 11 | |
| 7799092518 | Proteasome structure | -it is present in the cytoplasm -has two regulatory particles at the end of the tube and are tasked to select substrates, remove Ub for recycling and edit wrongly tagged proteins -the core particle has proteolytic enzymes and are like chymotrypsin after negatively charged amino acid residues | 12 | |
| 7799155916 | Ubiquitination Signals | 1. N-end Rule (half-life of a protein varied depending on its N-terminus based on its binding to E3- Methionine has the longest) 2. PEST sequences (proline, glutamate, serine, threonine) 3. Destruction boxes 4. Phosphorylation (external) 5. Denaturation/damage (oxidation)- (external) 6. Facilitators/Chaperones (e.g. HPV16 E6) (external) | 13 | |
| 7799327234 | HPV E6 | Forms a complex with target protein to increase the likelihood of ubiquitination - the presence of the viral E6 protein increases ubiquitination by recruiting E6-AP (associative protein), E3 ubiquitin ligase and deregulate p53 and up-regulates the cell cycle and the number of cells. -certain types of HPV are associated with cervical cancer other chaperones decrease the likelihood of ubiquitination | 14 | |
| 7799483503 | Parkinson's Disease | may be linked with the UPP pathway problem -characterized by Lewy bodies (protein deposits) in the brain that are not normally there -the lewy bodies cause a loss of neuronal cells & loss of dopamine, a neural transmitter treated by L-dopa Cause by: Parkin mutation: E3 type ubiquitin ligase mutation UCH-L1- mutation in ubiquitinase | 15 | |
| 7800766657 | Amino Acid Pools and Essential Amino Acids | 1. Free AA< Polymerized protein 2. 95% is replaced every 10 mins 3. Amino acids are transported in plasma (low mM) to intracellular AAs (about 10x more) | 16 | |
| 7801083805 | Free Amino Acid | plasma- glutamine and alanine cell- plasma, alanine, glutamate, glycine | 17 | |
| 7801772859 | Essential Amino Acids | PVT TIM HALL - have the most synthesis steps | 18 | |
| 7801829637 | Kwashiorkor | Due to insufficient protein or incomplete protein although total calories are OK mainly in children 1-3, the stomach bloats due to loss of plasma protein and fatty liver and the arms and legs are thin and skin is flaky -lose urea cycle enzymes, albumin and other plasma protiens causing their osmotic balance to be off | 19 | |
| 7801891345 | Protein Sources | Animal: 10-25%, easily digested, nearly complete AA's, chemical score is high Vegetable: 1-2% protein, incompletely digested, low in essential AAs (legumes and grains are complementary), chemical score is low Highest chemical score: milk and eggs | 20 | |
| 7801922967 | N-acetyl glutamate synthetase (NAGS) deficiency | inability to create urea from nitrogen from excess protein, treated with Carbaglu | 21 | |
| 7802202703 | Degraded Nitrogen from AAs | urea contributes about 16% of total protein and is the only level that changes as a result of changed protein intake * Note: carbons from AA's are liberated and stored | 22 | |
| 7804761378 | Positive Nitrogen balance | occurs during growth pregnancy and muscle building. Increased dietary protein, and increased body protein. Urea does not go up. | 23 | |
| 7804829708 | Negative Nitrogen Balance | -Insufficient protein or incomplete dietary protein. Urea and body protein go down. -trauma with high energy requirement. urea, dietary protein and muscle protein is the same, but the muscle protein being used is greater and is seen as an on demand protein for energy *LOSS of body protein *** a diet lacking in essential amino acids only will cause the body to catabolize the muscle protein creating both essential and non-essential AAs. This leads to excess non-essential AAs and the release of the excess nitrogen as excess urea than what is ingested. | 24 | |
| 7804859422 | Nitrogen removal steps | 1. Transfer to a common carrier 2. Ammonia is regnerated in the liver 3. Ammonia is incorporated into urea ammonia disposal or incorporation into AAs is determine by glutamate DH | 25 | |
| 7804867206 | Common carrier step | -Nitrogen is transferred to a carrier amino acid most common transfer of nitrogen is AA to aKG generating Glutamate and an aKeto acid the reaction uses PLP (rise from vitamin B6 and exchanges the keto group for a methylenyl-amine group) and an aminotransferase. Major keto-acids transfers are : aKG- glutamate, oxaloacetate- aspartate and pyruvate- alanine | 26 | |
| 7804988823 | Ammonia Regeneration in liver | In the mitochondria with a glutamate DH, glutamate is turned back into aKG and reduces NAD to form NADH and releases an ammonia which is incorporated into urea *abundant glutamate and aKG ATP/ADP transporters to transport things in and out of the mitochondria (while the GDH and aminotransferase reactions can happen anywhere in the body, urea formation with free NH4 happens only in the liver) | 27 | |
| 7805061647 | Asp and Glu NH4 production | glutamine-> glutamate via glutaminase asparagine-> aspartate via asparaginase | 28 | |
| 7805241523 | Methods of Ammonia Disposal | 1. Glutamine via glutamine synthase and is the major carrier of N in the blood *glutamine can only absorb only so much ammonia 2. Minor: glutamate by running glutamate DH -fixing ammonia especially in the brain, also muscle, lungs and adipose cells | 29 | |
| 7805394565 | Nitrogen Excretion | 1. NH4 from glutamine and the NH4 made in the liver mitochondria the glutamate DH and uses carbamoyl phosphate synthetase I, 2 ATP and a bicarbonate to make carbamoyl phosphate 2. Carbamoyl phosphte is added to orinthine and becomes citrulline which leaves the mitochondria and and combines with aspartate to become argninosuccinate 3. Aspartate uses another ATP and becomes argininosuccinate and then catabolizes to fumarate which leave and arginine which remains in the cycle. 4. the addition of water creates urea and orinthine to be recirculated back to the beginning of the urea cycle and is combined with carbamoyl phosphate to create citrulline one ammonia comes from aspartate and another from actual ammonia | 30 | |
| 7811575011 | Carbamoyl Phosphate Formation | Glutamate and acetyl CoA go to N-acetyl-glutamate using N-acetyl glutamate synthetase which uses arginine and stimulates the limiting step in the formation of carbamoyl phosphate | 31 | |
| 7812138387 | Glutamate Derivative Linkages | -orinthine can be used to make polyamine or spermine -recall that arginine is needed for nitric oxid (NO) production and creatine -orinthine can do amino transfer with alpha-ketoglutarate to make glutamate via glutamic gammma- semialdehyde which can make proline -glutamic gamma semi aldehyde can be made from glutamate **arginine is an essential amino acid because we cyphone it off as orinthine | 32 | |
| 7812595543 | Inoperative Urea Cycle | - rise in blood ammonia (glutamine levels rise) -treat by restricting protein and arginine supplementation (benzoate and phenylacetate/butyrate) -urea cycle connects to the TCA cycle *arginine, orinthine, glutamine, and proline are metabolically linked via a glutamate derivative | 33 | |
| 7816525776 | Pathway of Intracellular protein breakdown | 1. Hypercatabolic States (CHF, diabetes and myocardial ischemia, liver cirrhosis, trauma, senescence)- proteasome components are upregulated 2. Increased cytokines and catabolic hormones 3. Releases AAs from muscle and leads to muscle wasting (sarcopenia) and cachexia 4. The free AAs either go to global metabolism or to the liver for gluconeogenesis. 5. Gluconeogenesis and goes to the blood glucose which either goes to metabolism or to scavenger for oxygen free radicals via NADPH | 34 | |
| 7816745092 | Branch Chained Amino Acid Metabolism | liver is the first organ that metabolizes a significant amount of the amino acids from digestion from the intestine -low in branched-chain amino transferases to catabolize (leucine, valine and isoleucine) - excess branch-chained AAs are sent to the muscle and are used to for fuel and muscle catabolism *NH3 ends up as Glutamine or Alanine *production of alanine of the muscle goes back to the liver via the Cahill cycle for disposal into urea | 35 | |
| 7830912784 | Glutamine Usage | used in the intestine for fuel and promotes GI tract healing and nutritional supplementation with GI disorders HIV/AIDS, cancer and other critical illnesses KIDNEY uses glutamine for AMMONIA PRODUCTION using the glutaminase reaction, especially when pH control is needed *LIVER USES AMMONIA either to urea or glutamine Glutamate can form glutamate semialdehyde, which can form proline or form ornithine. Intestinal OTC produces citrulline which travels to the liver - some to kidneys, where arginine can be made. | 36 | |
| 7831114600 | Amino Acid Fates | Glycogenic: Alanine, Cysteine, Glycine, serine, threonine, asparagine, aspartate, phenylalanine, isoleucine, valine, arginine, glutamate, glutamine, proline *metabolized into pyruvate Ketogenic: leucine and lysine - serine-pyruvate aminotransferases is used to make alanine and hydroxypyruvate and use 2 more steps to it to glycerate-2-P and then to pyruvate | 37 | |
| 7873956682 | Dehydratases | act on AA's to produce different ketoacids serine--> pyruvate threonine --> alpha ketobutyrate via dehydratase and deaminase reactions both can be turned into glucose (succinyl CoA can become glucose as well) and are glycogenic substance | 38 | |
| 7873998326 | Alpha-Ketoglutarate AAs | 1. Arginine- glutamic gamma-semialdehyde is the intermediate which goes to glutamate 2. Proline- glutamic gamma-semialdehyde is also the intermediate which goes to glutamate 3. Glutamine- goes to glutamate 4. Glutamate- goes to alpha keto glutarate 5. Histidine- goes to glutamate |  | 39 |
| 7874053162 | succinyl CoA pathway | Threonine and Methionine converge at alpha-ketobutyrate Isoleucine- alpha-keto-beta-methylvalerate Valine- alpha-ketoisovalerate ---these intermediates all lead to propionyl CoA then succinyl CoA requiring BIOTIN and B12 *used also for degradation of fatty acids with an odd number of carbons -keto acid reactions use an enzyme similar to alpha KDH and require thiamine (TPP), lipoate and FAD |  | 40 |
| 7874104532 | BCAA Breakdown | The Breakdown of Branched Chain Amino Acids is via aminotransfer to form keto acids, and then the action of a BCAA dehydrogenase -isoleucine, valine and leucine Some individuals lack the enzyme complex (BCAA DEHYDROGENASE deficiency= maple syrup urine disorder MSUD), build up the keto acids & have urine that smells of maple syrup- autosomal recessive, mention treatment 40 different mutations noted in the gene | 41 | |
| 7874147623 | Leucine Catabolism | Breakdown of Leucine begins like other Branched-Chain AA and is first degraded into a ketoacid (alpha-ketoisocaproate) , then diverges to acetyl- CoA making it ketogenic |  | 42 |
| 7874197226 | Proprionyl CoA to Succinyl CoA conversion | -required biotin and Vitamin B12 -Threonine, valine, isoleucine or methionine can become propionyl- CoA -Diagnosis of a defect of the mutase reaction Methylmalonate appears in the urine- interferes with myelin sheath formation - Underlying problem can be complex: missing enzyme, or Vitamin B12 , its absorption, or its processing |  | 43 |
| 7874219862 | Adenosylcobalamine | is formed from Vitamin B12 (cobalamine) -R group (shown is adenosyl can be OH, CN , or methyl)-- OH and CN are the vitamin form -The adenosyl form of Vitamin B12 is needed for the methylmalonyl CoA mutase reaction in succinyl formation, methyl form is used for a different reaction -The vitamin (-OH) is absorbed using intrinsic factor, a glycoprotein in the cells lining the stomach (the actual absorption occurs in the small intestine) | 44 | |
| 7874301147 | Methylmalonic Acidemia | arises from several possible deficiencies: dietary intake of VitB12, lack of intrinsic factor, or an inability to convert to the adenosyl form, or deficient methylmalonylCoA mutase | 45 | |
| 7874320031 | Oxaloacetate pathway | Asparagine is degraded to aspartate using asparaginase and then to oxaloacetate using aspartate aminotransferase and PLP as a coenzyme (the NH4+ of aspartate is passed on to α-ketoglutarate to make glutamate in a aminotransfer reaction) |  | 46 |
| 7874573285 | Phenylalanine and Tyrosine Metabolism | metabolized to both fumarate (glucogenic) and acetoacetate (ketogenic) | 47 | |
| 7874593660 | Phenylketonuria (PKU) | deficiency in 1. phenylalanine hydroxylase 2. the ability to recycle tetrahydrobioterin (synthesized from GTP) using dihydrobiopterine reductase and NADPH cofactor both used to convert phenylalanine to tyrosine when metabolism is blocked phenylpyruvate or phenylpyruvic acid (leading to phenylacetate and phenyllactate) are produced symptomology: 1. Urine is typically musty 2. High levels cause brain damage as it affects neurotransmitter (serotonin) synthesis and transport/ cognitive impairment 3. Treatment protein restriction, no excess protein in the diet; diet low in phenylalanine with coenzyme supplement 4. Supplement with tyrosine *Monitor the body: bodily trauma will cause the body to release large amounts of muscle protein that is rich in phenylalanine and can overwhelm the body even with the supplement | 48 | |
| 7927534981 | Catecholamine: Dopamine | made from TYROSINE using Tetrahydrobiopterin in the hydroxylase reaction making Dopa. Dopa is changed to dopamine using the aromatic amino acid decarboxylase using PLP and releasing CO2 Dopamine is associated with pleasure. made in the brain | 49 | |
| 7927682493 | Thyroxine | tyrosine is attached to a thyroglobulin protein and is iodized using thyroid peroxidase to make 2 diiodotyrosine; the two diiodotyrosine are added together to make thyroxine this hormone is important for regulating metabolism made in the thyroid gland | 50 | |
| 7927709141 | Melanin | this is made from tyrosine using tyrosinase (tyrosine 3-mono-oxygenase) structure looks like a combination of tyrosine and DOPA albino patients lacking this enzyme do not have melanin pigments in their skin and eyes made in the skin | 51 | |
| 7927795794 | Synthesis of Glycine and Cysteine from Serine | -synthesis of these two proteins require one carbon transfers (important also in nucleotide and lipid metabolism) -Biotin transfers a CO2 group - S-adenosyl methionine transfers the methyl group -Tetrahydrofolate (THF) can transfer one-carbon fragments that have varying levels of oxidation (formic acid to methyl groups) -glycine can be synthesized de novo using NH4, CO2, NADH and 5,10-methylene THF using GLYCINE SYNTHASE -serine can be made using 3-phosphoglycerate and can also be a de novo synthesis for glycine using serine hydroxymethylase -if there is no need for one-carbon fragments, the process goes in reverse and pyruvate is made | 52 | |
| 7927920857 | Tetrahydrofolate | -derived from the vitamin folic acid -vitamin form carries 2-7 glutamyl residues on the carboxyl end -free folic acid has 1 glutamyl residue -free folic acid (diet form or dihydro folate) is reduced to THF by dihydrofolate reductase -In the blood plasma, THF is transported as the 5-methyl derivative -polyglutamyl form INSIDE the cells is best for 1-carbon transfers -receives the one carbon fragments from glycine, serine and histidine on the N5 or N10 -different levels of oxidation can be seen and interconverted between all one-carbon fragments except the 5-methyl THF. The 5-methyl THF has to be converted to THF using the methionine synthase (MTR or methylene-THF reductase) using methylcobalamine -if vitamine B12 levels are low, there will be a decrease in MTR and a decrease in THF -serine -> glycine reaction using THF and serine hydroxymethylase yields 5,10- methylene THF OTHER INVOLVEMENT: -pyrimidines (nucleic acid synthesis)- Methotrexate, a structural analogue of folate interferes with the growth of cancer cells in the synthesis of pyrimidines -low folate slows DNA synthesis -phospholipids -REGENERATION OF METHYL GROUPS IN SYNTHESIS OF METHIONINE FROM HOMOCYSTEINE USING MTR AND METHYLCOBALAMINE (B12) | 53 | |
| 7932118010 | S-adenosyl methionine (SAM) | -created by methionine adenosysltransferase -can donate a methyl and after donation of the methyl becomes S-adensosylhomocysteine -participates in the methylation of histones, DNA, RNA, tRNA, choline, epinephrine and creatine -is used in the production of catecholamines norepineprine and epinephrine made from dopamine, specifically making epinephrine from norepinephrine after it has been synthesized from dopamine |  | 54 |
| 7932241130 | urine content | urea, creatinine, uric acid and ammonia | 55 | |
| 7932471298 | Synthesis of Creatine/Creatinine | *creatine phosphate is a high-energy compound that regenerates muscle ATP AA's used: arginine, glycine, methionine (SAM) in the kidney, and liver to make creatine; creatine is shuttle to the brain, heart and skeletal muscle -creatine is phosphorylated to phosphocreatine using ATP and creatine kinase -phosphocreatine spontaneously cyclizes to form creatinine which is not metabolized further and is excreted in urine and is an indicator of muscle mass (1-2% of muscle creatine is converted to creatinine) -creatinine is removed from the blood by the kidneys creatine is used for CHF, depression, bipolar disease, parkinson's disease |  | 56 |
| 7932995139 | regeneration of methionine from SAM | -after SAM is used (methyl transferred), it creates S-adenosylhomocyteine and this is hydrolyzed to adenosine and homocysteine 1. homocysteine is methylated by methionine synthase (MTR) using methylcobalamine as the coenzyme (this is made using methyl-THF) 2. transfer of a methyl group from a choline derivative (betaine) *methionine is still and ESSENTIAL AA | 57 | |
| 7933108353 | Cysteine Synthesis from Homocysteine | -made from the combination of Homocysteine and serine using PLP and cystathionine B-synthase this is the only reaction that generates cysteine, in its absence, cysteine is an essential AA | 58 | |
| 7933143000 | Taurine | derived from cysteine and is an important component of the substances found in bile (conjugated with cholate) -found in the lower intestines and in other tissues -made via 3 steps of decarboxylation and oxidation | 59 | |
| 7933195214 | Folate Trap | -The (methionine synthase) methylene THF reductase reaction that produces methylTHF is essentially irreversible -The only way to return the THF in the methyl THF form back to the THF pool is through the Vitamin-B12 dependent methionine synthase reaction. -A VitaminB12 deficiency therefore causes a secondary deficiency in folate | 60 | |
| 7933206448 | Homocystinuria (HomocystINE) | -homocysteine in the cells becomes homocystine in the urine and is associated with a high risk of arterial disease, tall and thin and have problems with vision -there is a defect in the cystathione synthetase to create cysteine and patients may need to supplement with cysteine b/c is it an essential AA to them -alternative treatments 1. PLP (B6)- cofactor for cystathione synthetase 2. choline or betaine- leads to the methylation of homocysteine and the creation of methionine and reformation of homocysteine)---less build up of homocystINE 3. supplement with folate for methionine synthase 4. low protein diet or formula low in methionine | 61 | |
| 7934115373 | Nucleotide Important Jobs | 1. activated precursors of DNA and RNA 2. components of three major coenzymes (NAD+, FAD and CoA) 3. ATP is universal currency of energy 4. GTP powers movement of macromolecules 5. Derivatives are activated intermediates in biosyntheses events (UDP-glucose --> glycogen; CDP- diacylglycerol --> phosphoglycerides) | 62 | |
| 7934194610 | De Novo Purine Synthesis | -happens in the liver and placenta 1. G6P goes into the pentose-phosphate shunt and creates ribose-5-phosphate which adds to ATP to from PRPP using PRPP SYNTHASE (this is a key intermediate for both purines and pyrimidines). Regulation is dependent of the concentration of nucleotides 2. REGULATION: amidophosphoribosyltransferase (HGPRT and APRT) reaction of the salvage pathway shuts off this step)- The replacement of the pyrophosphate of the PRPP with the amine of glutamine makes 5-phosphoribosylamine using an glutamine PRPP amidotransferase that is inhibited by end products (this is the committed step in purine nucleotide biosynthesis- salvage pathway decreases the rate of de novo synthesis) 3. The purine ring is assembled around the amino group of the phosphorobosylamine and the ribonucleotide inosinic acid (IMP) is produced using 4 ATP, Glycine, 2 formyl THF, glutamine, CO2 and an aspartate. The first atom of the purine ring forms the glycosidic bond and is an important regulatory step. AMP and GMP production inhibits this step 4. IMP, the first purine synthesized (also holding a hypoxanthine base), can be converted into AMP (using GTP) or GMP (using ATP). This makes it so the abundance of one nucleotide triphosphate ensures the production of the other and AMP and GMP. 5. GMP and AMP can be converted into triphosphates using base specific monophosphate kinases and the non-specific nucleotide diphosphate kinases along with a triphosphate of the other nucleotide as in step 4. To be active most nucleotides must be in triphosphate form *all reactions occur in the cytosol | 63 | |
| 7938529384 | Salvage Pathway- Purines | -occurs in outside of the liver, and recycles the bases in the body. Chemotherapeutic agents are introduced through this pathway; nucleosides and bases can also come from diet 1. Direct conversion reaction: HGPRT: guanine base + PRPP = GMP + PPi Hypoxanthine base + PRPP= IMP + PPi APRT: Adenine base + PRPP= AMP + PPi 2. Reversible Conversion of Base -> Nucleosides -> Nucleotides -this pathway is less significant **nucleoside phosphorylase: nucleoside N + Pi= base + R1P nucleoside kinase: nucleoside N + ATP= NMP + ADP ** phosphorylase is rarely used to salvage a base, the predominant direction is degradative | 64 | |
| 7938645771 | AZT Triphosphate Formation | formed by the sequential action of thymine kinase (nucleoside), thymidylate kinase and nucleotide diphosphate kinase | 65 | |
| 7938651646 | Origins of the atoms in the purine ring |  | 66 | |
| 7938677138 | Catabolism of Purines | 1. conversion of nucleotides to nucleosides using phosphatase (AMP= adenosine(nucleoside) + Pi) 2. Adenosine, 2-deoxyadenosine and 6-aminopurines are deaminated by adenosine deaminase using water to form inosine 3. Purine nucleoside phosphorylase- yields the base (hypoxanthine) and ribose-1-phosphate (the sugar) 4. Formation of uric acid from the oxidation of hypoxanthine to xanthine and then to uric acid using xanthine oxidase. ** the breakdown product of GMP is converted to xanthine by guanine deaminase | 67 | |
| 7938815962 | Gout | uric acid levels in the blood are normally high (prevent cancer caused by oxidants and free radicals), gout occurs when levels are too high causing urate deposits in the joints and kidneys -caused by overproduction of purines or a failure to excrete uric acid when renal function is impaired Enzyme defect: 1. HGPRT- causes PRPP to accumulate and de novo synthesis 2. PRPP synthase that is not susceptible to feedback inhibition by purine nucleotides, leads to activation of de novo pathway 3. Glucose-6-phosphatase deficiency: leads to increased usage of the PPS and excessive production of R5P and therefore PRPP | 68 | |
| 7938931380 | Allopurinol | analogue of hypoxanthine lowers uric acid levels in the blood and is a competitive inhibitor of xanthine oxidase. This leads to the accumulation of hypoxanthine and xanthine that are more soluble in the urine and are easily excreted | 69 | |
| 7938940692 | Lesch-nyhan syndrome | - infants lack HGPRT -leads to self mutilation, mental illness and gout -marked increase of purine de novo biosynthesis -HGPRT has the highest activity in the brain, so can be alluded to the neurological issues -allopurinol is used to treat the gout, but nothing can be done about neurological symptoms | 70 | |
| 7938972242 | Adenosine deaminase (ADA) deficiency | -causes sever combined immunodeficiency (SCID) -patients lack both B and T lymphocytes and die by the age of 2 -associated with a build up a dATP (inhibitor of ribonucleotide reductase and DNA synthesis) -block active of immune response, lymphocytes are sensitive to levels of dATP -retroviral vectors can be designed for use in gene therapy | 71 | |
| 7938993398 | Inhibitors of purines | -sulfonamides: and analogue of p-amoniobenzoic acid, a component of folate, and interferes with folate acid synthesis in bacteria -6-mercaptopurine: analogue of hypoxanthine and is used as an antitumor drug and is converted to a nucleotide by HGPRT; this pathway sequesters PRPP and is a competitive inhibitor of IMP in GMP and AMP synthesis pathways | 72 | |
| 7939307356 | Pyrimidines | thymine and cytosine, the ring is synthesized before being attached to PRPP ring is made of: Aspartate, glutamine, and bicarb stages of synthesis: 1. the formation of UMP 2. the conversion of UMP to other pyrimidine nucleotides Usages: -used to activate sugars -used in the pathway to create phospholipids (phosphatidylglycerol phosphate and phosphatidylinositol) - contributes carbamoyl phosphate which can enter into the urea cycle | 73 | |
| 7939317226 | De Novo Pyrimidine Synthesis | 1. [Carbamoyl phosphate] is is created using bicarbonate, glutamine and 2 ATP using the CARBAMOYL PHOSPHATE SYNTHETASE II (CPSII)- this is a major regulatory step *inhibited by UTP and is stimulated by PRPP and ATP (establishes the purine and pyrimidine balance)* 2. [N-carbamoyl aspartate] is formed using carbamoyl phosphate and aspartate and the enzyme ASPARTATE TRANSCARBAMOYLASE 3. [Dihydroorotatic acid] is formed by the closure of the ring using dihydroorotase *these first three enzymes are all domains of the same protein* 4. [Orotate] is formated using NAD+ and Dihydroorotate DH 5. Orotic acid reacts with PRPP to form OMP catalyzed by orotate phosphorybosyltransferase 6. UMP is created from OMP using OMP decarboxylase; UMP is converted to UTP by nucleotide kinases and uses ATP as the donor *UMP is an inhibitor of OMP decarboxylase and causes the accumulate of orotate ***OMP decarboxylase and orotate PRT are located on the same enzyme 7. CTP is made of UTP when the amine nitrogen of glutamine is transferred to the C4 carbon of the UTP ring | 74 | |
| 7939464422 | Salvage pathway- Pyrmidines | -because orotate PRT functions like HGPRT and APRT, if there is a base already present, OPRT can be used to salvage it, but there is another pathway present to divert nucleic materials from degradation and involved two steps instead of the one for purine salvage (base + PRPP) 1. pyrimidine + NUCLEOSIDE PHOSPHORYLASE and ribose-1 phosphate = pyrimidine-ribose 2. Pyrimidine-ribose is phosphorylated with a kinase and ATP to yield the nucleotide (pyrimidine-ribose phosphate); the kinase is thought to be the salvage enzyme because it diverts from degradation | 75 | |
| 7939502351 | Pyrimidine Catabolisim | -occurs manly in the liver yield soluble products 1. Converted to nucleosides by phosphatases 2. Cytidine is converted to uridine by cytosine deaminase 3. Uridine and thymidine (nucleosides) are converted to free bases by pyrimidine nucleoside phosphorylase 4. Uracil and thymine (bases) catabolism proceed to B-alanine (acetyl CoA) and B-Aminoisobutryrate (succinyl CoA) *unlike purine rings, the pyrimidine rings are opened during catabolism -B-aminoisbutryrate (thymine) can be used to monitor cell turnover following radiation therapy | 76 | |
| 7939611727 | deoxyribonucleotide formation | -takes place during the S-phase -can be converted by reducing the ribose moiety using ribonucleotide reductase (inhibited by dATP and uses Mg and has sulfhydril groups) for all four nucleotides -the electron donor is thioredoxin (active sulfhydryl groups) -sulfhydryl groups are regenerated with NADPH and a reaction catalyzed by thioredoxin reductase that uses FAD as a cofactor | 77 | |
| 7939666982 | hydroxyurea | an antineoplastic agent and inhibitor of DNA synthesis and inactivates the enzyme RIBONUCLEOTIDE REDUCTASE | 78 | |
| 7940127916 | Methotrexate | an analogue of folic acid (dietary form) that has a very high affinity from dihydrofolate reductase. The binding is irreversible and the enzyme is inactivated failure to regenerate THF inhibits TTP synthesis -effective against leukemia, and things that have high rates of division (psoriasis and proliferative skin disease) -normal cells fast dividing cells are rescued by providing 5-formyltetrahydofolate to bypass the regeneration blockage other inhibitor of dihydofolate reductase: -aminopterin -trimethoprim | 79 | |
| 7940320713 | synthesis of thymidine nucleotides | TMP is formed by the methylation of dUMP and is catalyzed by thymidylate synthatase using Folate H4 (N5, N10 methylene tetrahydofolate) -formed from the reaction of serine to glycine. Folate H4 is oxidized back to dihydrofolate and the enzyme dihydrofolate reductase is required to do this (inhibited by dihydrofolate analogue methotrexate) dUMP can be formed by dUTP and diphosphohydrolase and water releasing dUMP and pyrophosphate | 80 | |
| 7940550098 | Orotic aciduria | -rare autosomal recessive trait -caused by the accumulation of excessive amounts of orotic acid caused by a decrease in activity of orotate decarboxylase or orotate PRT -high levels of orotic acid in the blood lead to anemia, growth retardation and inability to synthesized UMP - can be corrected by the administration of uridine and can lead to UMP | 81 | |
| 7940866703 | Control of Deoxyribonucleotide synthesis | -lack of dNTP is lethal, while and excess is mutagenic the enzyme ribonucleotide reductase is regulated to achieve balance: 1. ATP: positively regulates dUDP and dCDP 2. dTTP: positively regulates dGDP and negatively regulates dUDP and dCDP 3. dGTP: positively regulates dADP and negatively regulates dGDP and dUDP 4. dATP: negatively regulates the synthesis of all this is how the balance of nucleotides is achieved | 82 | |
| 7940893632 | 5-fluorodeoxyuridine | converted to fdUMP by thymidine kinase and binds tightly to thymidylate synthetase blocking TMP synthesis | 83 | |
| 7941752697 | Long term complication of diabetes | 1. diabetic eye- major cause of blindness in working age adults 2. Diabetic feet- lots of amputations a year 3. Diabetic kidney- 30-50% develop kidney disease, proteinuria 4. Diabetic heart- coronary artery disease risk is 4 times greater | 84 | |
| 7941773716 | Diabetic glucose control | -starts higher, goes higher after eating and comes down more slowly Therapies: 1. alpha-glucosidase inhibitors (acarbose): glucosidases turn carbohydrates to glucose -treats type 2 diabetes, used along with diet and exercise 2. SGLT2 inhibitors found in the kidney, and stops the body from resorbing glucose; associates with decrease in deaths and cardiac problems 3. Insulin, first -rapid acting- lysine pro -long acting- arg *insulin 1. affects uptake by moving GLUT4 in the muscle an adipose tissue to the plasma membrane to increase the Vmax of transport in the cell 2. Decreases glycogenolysis 3. Decreases gluconeogenesis | 85 | |
| 7947161299 | Insulin | produced by processing in Beta-cells by the processing of precursors 1. preproinsulin- has a signal sequence, C peptide, alpha and beta chain 2. Proinsulin has lost the signal sequence and disulfide bonds form in the RER 3. Insulin loses the C-peptide In the golgi and is stored in secretory granules *c-peptide indicates insulin secretion levels from beta cells because it is more stable and has a longer half life than insulin | 86 | |
| 7947226485 | Insulin production and secretion | 1. glucose controls insulin in the pancreas where there is glucokinase- the production of ATP causes the opening of an ATP Dependent potassium channel depolarizing the membrane as calcium flows out allowing calcium to flow in and allow for the release of the vesicles *sulfonyureas and meglitonides where used to target the potassium channel 2. Incretins Hormones produced in digestive track GLP1 and G1P produced by endocrine cells (L and K) (injecting glucose causes less of an affect then ingesting glucose) -GLP1/GIP goes to the pancreas binds to its G-protein receptor and acts on the Beta cell to create cAMP and PKA, this has the same effect as ATP and Ca 2+ and insulin granules are released *exenatide- is a more stable GLP1/G1P analogue *Sitagliptin (Januvia) a DPPIV protease inhibitor that prolongs GLP1/G1P life *Interest in GPCR regulators that affect cAMP | 87 | |
| 7948351086 | Types of Diabetes | -type 1 (5-10%)- loss of beta cells -type 2 (90%- insulin resistance or B cell failure) -gestational diabetes (4% of pregnancies) -Other (MODY , endocrine diseases problems with glucokinase) | 88 | |
| 7948446895 | Type 1 Diabetes | -usually less than 20 -genetic susceptibility -not usually obese -B-cells are absent -they have GAD+ autoimmunity -have little or no plasma insulin -that have a normal response to insulin -severe fasting hyperglycemia -have DKA ketoacidosis, do not have the insulin to supress ketone body production * when you are acidotic, you have very shallow breaths, but once you reach kussmaul breathing, it becomes very labored precursor to patient dying *can stop acidosis by excreting amonia in the urine -treatment is insulin | 89 | |
| 7948469427 | Type 2 Diabetes | - most older than 40 - have genetic susceptibility -they are commonly obese - the beta cells are preserved initially -they usually do not have autoimmunity - they have a low to high plasma insulin - their response to insulin is generally reduces - their fasting hyperglycemia is variable -They usually do not have ketoacidosis because you only need 10% of insulin to suppress ketoacidosis and can undergo hyperglycemic hyperosmolar synd (HONK-HHS) -hypertriacylglycerolemia- lipid triad: loss of insulin results in lower VLDL leading to decreased activity of lipoprotein lipase and increased activity of hormone sensitive lipase activity, elevated triglycerides, low HDL because the liver secretes more VLDL because there is not enough and HDL loses APO-E and gets degraded in the kidney and small, dense LDL, made by a liver protein -treatment is change in diet, oral antidiabetics and insulin Osmolarity= normal is 290 | 90 | |
| 7948982311 | Metformin | reduces hepatic glucose output by acting on complex one in the mitochondria to affect AMP levels, the most commonly used diabetic drug | 91 | |
| 7948993226 | problems of hyperglycemia | 1. Glucose reacts with metals to generate reactive oxygen species (ROS)- generates athosclerotic plaques and anemia 2. The polyol pathway where glucose is converted to sorbitol then to fructose, creates a surplus of sugar alcohol which affects the NADPH/NADP+ ration, Galatitol causes cataracts in infants, cataracts can also be caused by osmotic issues in infants 3. Glycation generates protein adducts (HbA1c) leading to advanced glycation endproducts (AGE) that are themselves reactive and can cause tissue damage (HbA1c) shows how patient is controlling glucose of a 2-3 month period normal AIC percentage is 4-6% | 92 | |
| 7949336813 | Insulin signaling | -insulin established multiple signal cascades via a cell membrane tyrosine kinase that acts as its receptor Effector molecules 1. TKR phosphorylates IRS-1 that is the adaptor proteins 2. IRS-1 can activate RAS- leading to other protein kinases activating transcription factors 3. IRS-1 can also activate the p85/p110 complex leading to PIP3K (oncogene) 4. PIP3K can activate PDK1 protein kinase phosporylates AKT (oncogene) leading to GLUT4/IRAP vesicles and more transcription factors *insulin can also shoot transcription factors out the nucleus into the cytoplasm; this is an inhibitory mechanism | 93 | |
| 7949527347 | Insulin resistance | 1. Genetic causes (mutation in IRS-1) 2. Changes in free fatty acid levels 3. Proinflammatory cytokines (TNF-alpha, IL6) blunts the response to insulin by inhibiting things in receptor pathway 4. Alterations in adipokines ( decrease in adiponectin and increase in resistin) | 94 |
