Biochem - Unit II - Review

Diabetes

Mellitus

an elevated fasting blood glucose

type 1 and 2

• 1. transcription of insulin gene in nucleus
• 2. mRNA moves to cytosol and translating the N-terminal signal sequence on ribosome. The signal helps the complex to move on to RER.
• 3. complete translation of mRNA, preproinsulin produced
• 4. signal sequence cleaved off preproinsulin, forming proinsulin in RER lumen
• 5. proinsulin transferred to Golgi, where it is further cleaved into insulin and C-peptide.
• 6. insulin and C-peptide packed into vesicles.
• 7. insulin and C-peptide are released via exocytosis.

• glucose and insulin are both at the lowest level before the meal, rise to the peak shortly after the meal, and then slowly fall back to the base level.
• glucagon is at high level before meal, peaked during meal, then drops to the lowest level.
• inverse relationship between insulin and glucagon

• Glucose (++)
• FAs, AAs (+)
• Epinephrine (-)

• insulin binds to membrane receptor
• binding stims a cascade of actions, resulting in the recruitment of GLUT-4 from intracellular pool to membrane
• insulin-mediated GLUT-4 increases blood glucose uptake
• when glucose level drops, GLUT-4 move away from membrane to intracellular space
• vesicles containing GLUT-4 fuse to form storage organ, endosome

• no insulin
• high glucagon

• Glucose (hyperglycemia; gluconeogenesis + decreased glucose uptake)
• ketone bodies (ketosis: adipose tissue fatty acid-> hepatic ketogenesis)
• chylomicrons
• VLDLs

• polyuria
• polydipsia
• polyphagia
• Hb A_1C > 6.5 mg/dL
• fasting blood glucose > 126 mg/dL
• when blood glucose>180mg/dL, glucose can be found in urine with loss of water

• resistance to insulin in tissues (low glucose take up, high gluconeogenesis)
• hyperglycemia
• β-cells produce inappropriate amount of insulin
• later on β-cell failure

• Years before diagnose, obese and developing insulin resistance.
• When diagnosed, hyperglycemia and compensatory hyperinsulinemia.
• Years after, β-cell disorder, dramatic decrease in insulin production and worsening of hyperglycemia.

autoimmune destruction of b-cells

obese, inflammatory factors, insulin resistance

• metabolism: hyperglycemia, ketoacidosis.
• long term complications:
• - macro-vascular
•    - cardiovascular disease, stroke
• - micro-vascular
•    - neuro-, retino-, and nephro-pathy

• integral protein
• transmembrane part: coiled-coil dimer stabilized by Van der Waals interaction
• cytosolic part: basic AA, positive charges stabilized by intracellular negativity

• lipid anchored proteins bind to membrane lipid via covalent bonds
• peripheral proteins attach to transmembrane proteins via protein-protein interaction. no covalent bond, weaker interaction

• signal sequence peptidase
• translocon
• stop-transfer anchor sequence

• phenylalanine Phe
• valine, Val
• threonine, Thr
• tryptophan, Trp
• methionine, Met

• leucine, Leu
• isoleucine, Ile
• lysine, Lys
• histidine, His
• *arginine, Arg

• protein + ubiquitin + ATP -> ubiquitined-protein (UP) + AMP + PPi
• proteosome unfolds UP, de-ubiquitins it, and breaks it down to polypeptide fragments, at the cost of ATP
• polypeptides are further degraded by nonspecific proteases into AAs

pyrophosphate

• Protein
• ↓ pepsin
• polypeptides and AAs
• ↓ trypsin/chymotrypsin/elastase/carboxypeptidase
• oligopeptides and AAs
• ↓ aminopeptidase, di-/tri-piptidases
• AAs

both stimed by dietary lipids and proteins

• CCK stims
• gallbladder -> bile,
• pancreas -> enzymes;
• inhibits gastric motility

• secretin stims
• pancreas -> bicarbonate

7

• Cynstine, Ornithine, Arginine, Lysine (last 3 dibasic)
• the resorption of the AA, esp cystine at the proximal convoluted tubule
• cystine percipitates in acidic urine, forming stones (calculi)
• cystinuria

Dermatitis, diarrhea, dementia, death

deficiency of niacin -> NADP+

• deficiency in tryptophan absorption
• try ->... -> NADP+
• results in pellagra

niacin and tryptophan

pallegra

• negative
• protein malnutrition
• physical
• mental: lethargy, apathy, irritability
• physiological
• final stages
• treatment

• aminotransferase / transaminase
• α-ketoglutarate
• α-keto acid + glutamate
• 

• ALT (alamine transaminase)
• AST (aspartate transaminase)
• <40IU/L

• pyruvate, donate; glutamate
• aspartate, receiver; aKG
• PLP: pyridoxal phosphate

• glutamate-> aKG
• glutamate dehydrogenase
• NAD+ -> NADH
• NH3
• ADP stim; GTP inhibits
• NADPH -> NADP+
• removing NH3 when urea production can't deplete NH3 in time

• brain
• L-serine

• FAD
• oxidative deamination of D-AA
• a-keto acids, ammonia, and hydrogen peroxide

schizophrenia

• Free NH3 + glutamate -> glutamine; E: glutamine synthetase; ATP required.
• Glutamine-> blood->liver->glutamate + Free NH3; E: glutaminase
• NH3-> -> urea

• Free NH3 + aKG -> glutamate; E: glutamate dehydrogenase
• glutamate + pyruvate -> aKG + alanine; E: ALT; pyruvate comes from glycolysis and metabolism of AAs w/ branched side-chain
• alanine->blood->liver->pyruvate while aKG->glutamate w/ALT
• glutamate->aKG+NH3; E: glutamate dehydrogenase
• NH3->->urea
• pyruvate->->glucose->blood->peripheral tissue such as muscle

glutamine carries nitrogen from tissue to liver, then gives up NH3 directly

alanine carries nitrogen from tissue to liver, alanine-glucose cycle involved, nitrogen is transferred to gKG->glutamate, from which NH3 is released.

• 1. HCO3-, NH3, ATP -> carbamoyl phosphate (C1N1); E: CPSynthetase I
• 2. ornithine+CP (C1N1)->citrulline (C1N1)+Pi
• citrulline: mitochondria->cytosol
• 3. oxaloacetate + glutamate -> aspartate(N) + aKG
• 4. citrulline(CN)+aspartate+ATP -> arginosuccinate (CN2)
• 5. arginosuccinate(CN2)->fumarate + arginine (CN2)
• fumarate->malate->oxaloacetate
• 6. arginine+H2O->ornithine+CO(NH2)2
• ornithine: cytosol->mitochondria

• phenylbutyrate -> phenylacetate
• phenyacetate binds with glutamine, the common NH3 carrier, and the product is excreted via urine

• ketogenic: Leu, Lys
• glucogenic and ketogenic: Tyr, Phe, Try, Ile
• glucogenic: all the others

• pyruvate
• acetyl CoA
• succinyl CoA
• oxaloacetate
• fumarate
• aKG
• acetoacetate

• Asn - asparaginase -> Asp - AST -> oxaloacetate
• asparaginase, breaks down any systemically generated Asn, so there is no Asn supply in leukemia cell, which will be starved to death.

tyrosine - hydroxylase + BH4 - - decarboxylase -> dopamine - hydroxylase -> norepinephrine - methyltransferase -> epinephrine

cocaine

• COMT and MAO
• inhibiting MAO

tryptophan - BH4 and hydroxylase -> 5-OH tryptophan - decarboxylase -> serotonin

prozac inhibits the reuptake of serotonin, thus prolongs its action

• phenylketonuria or hyperphenylalanemia
• deficiency in the pathway of converting Phe to Tyr, which leads to Phe accumulation and entering alternate pathway, forming phenylpyruvate, phenylacetate, phenyllactate, high level in urine
• Reduction in tyrosine production reduce melanin formation -> depigmentation (hypopigmentation). Also has CNS symptoms.
• treatment: Phe free diet

• BH4 (TetraHydroBiopterin)
• BH2 -> BH4
• catecholamines
• serotonin

• deficiency in the dehydrogenase (oxidatively decarboxylation) for the α-keto acid, the intermediate of branched chain
• AAs' (Leu, ILe, Val) metablism, results in blood and urine accumulation of these AAs and the α-keto acids, and a maple syrup odor in the urine (Ilu).
• Symptoms: feeding, muscle tone, CNS (Leu, a-Kic acid), can be fatal, treatment can be too late
• Treatment: limit the amount of branched chain AA

• deficiency in a copper-requiring tyrosinase
• depigmentation in skin, hair, eyes; lightphobic; skin susceptible to sun burn and skin cancer; impaired vision
• treatment: avoid UV exposure

• defects in homocystine (Hcy) metabolism
• symptoms: high blood and urinary level of Hcy and Met. lens dislocation, long limb and fingers, intellectual disability, risk of developing blood clots.
• treatments: limit Met in diet and supplement B6, B12, folate.

• deficiency in homogentistic acid oxidase, causing accumulation of HA (homogentistic acid), an intermediate of tyrosine degrading.
• symptoms: urine exposed in air oxidized to black; deposition of black pigment in cartilages and collagenous tissue; major joint arthritis
• treatment: diet with low Phe and Tyr.

• ACh binds to ACh GPCR->PLC->IP3->Ca-Camodulin->NO synthesis->NO release
• NO -> NO receptor, stims GTP-> cGMP + PPi, cGMP activates PKG -> -> stims smooth muscle relaxation

• glucose enters cell via GLUT2
• glucose--glycolysis -->pyruvate + ATP
• ATP sensitive K chan closes
• cell depolarizes
• voltage-sensitive Ca chan open
• influx of Ca induce fusion of insulin-containing vesicle to cell membrane and release of insulin

• insulin->insulin receptor
• activates the intracellular β-domain which has tyrosin kinase function
• tyrosin kinase auto-phosphorylate and becomes activated
• activated tyrosin kinase phosphorylates other tyrosine-protein (eg insulin receptor substrate, IRS)
• activated target protein further activates other pathways, cause
• increase in
• glucose uptake
• glycogen synthesis
• lipid synthesis
• protein synthesis
• and decrease in
• gluconeogenesis
• glycogenolysis
• lipolysis

• IP3 --IP3 kinase--> PIP2
• inactive PKB (Akt) binds to PIP2, becomes partially active
• PIP2 also binds to PDK1
• activated PDK1 and PDK2 together activate partially activated PKB to fully activated

insulin binds to ->insulin receptor activates -> IRS stims -> PI3K -> PIP2 -> PDK -> AKT -> phosphorylates AS160 ->AS160-P promotes -> RabGTP -> receptor containing endosomes fuse with membrane

• insulin stims / glucagon inhibits
• glucokinase
• phosphofructokinase
• pyruvate kinase

• epinephrine and AAs stim
• glucose and insulin inhibit

• glucagon->receptor->adenyl cyclase->cAMP-> PKA c unit -> phosphorylate various enzymes -> ->
• gluconeogenesis
• glycogenolysis
• FA oxidation
• ketogenesis
• uptake of AA
• inhibit glycogenesis

epinephrine ->-> cAMP -> PKA -> active hormone-sensitive lipase -> diacylglycerol -> monoacylglycerol + FA

• gluconeogenesis: cortisol = glucagon
• glycogenolysis: (nor)epinephrine > glucagon