Biochem-TCA
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- intermediates of tca cycle
- citrate, isocitrate, alpha-ketoglutarate, succinyl coA, succinate, fumarate, malate, oxaloacetate (cindy is kind so she forgives more often)
- key enzymes of regulation in tca cycle (and what reactants they convert to what products)
- 1) citrate synthase (acetylcoA to citrate), 2) isocitrate dehydrogenase (isocitrate to alpha-ketoglutarate), alphaKGdehydrogenase (alphaKG to succinylcoA)
- regulation citrate synthase
- (TCA cycle, acetylcoA to citrate) inhibited by ATP (NADH, succinyl coA, fa co A, + ADP)
- regulation of isocitrate dehydrogenase
- (isocitrate to aKG) inhibited by NADH and ATP, activated by ADP and Ca [no succinylcoA]
- regulation of aKGdehydro
- (aKG to succinyl coA) inhibited by succinyl coA, NADH, ATP; activated by Ca
- cofactors of aKG dehydro
- same as PDH (B1,2,3,5,lipoic acid)
- energy produced from TCA
- 3 NADH, 1 FADG2, 1GTP, (2CO2) for total of 12 ATP
- steps at which energy produced TCA
- succinyl coA to succinate (1GTP), succinate to fumarate (FADH2), (3NADH) at malate to oxaloacetate , isocitrate to aKG, and aKG to succinylcoA
- what comes in in the succinyl coA step
- odd chain FA (via propionylcoA and methylmalonylcoA)
- aKG can be diverted from TCA to
- AA (via glutamate transamination/deamination)
- citrate can be diverted from TCA to
- fa (this is how acetyl coA is transported out of mitochondria for fa synthesis--malonyl coA + acetyl coA)
- amino acids can come into TCA at
- fumarate step (fumarate also byproduct of urea cycle)
- oxaloacetate may come from
- aspartate (via transamination/deamination)
- rxn of transamination/deamination
- aa come in as glutamate and on conversion to aKG give off NH4 to urea cycle. then aKG converted back to glutamate while aspartate converted to oxaloacetate, enz PLP requiring B6.
- steps of pentose P path (HMP shunt)
- Glu6P to ribuloseP via G6PD (producing NADPH), to Fru 6P
- ribuloseP can be used for
- nucleotide syn (converted to ribose5P)
- steps glycogen synthesis
- Glu1P to UDP-Glu to Glycogen (where Glu1P converted from Glu6P of glycolysis)
- regulatory enzymes of glycolysis
- PFK (Fru6P to Fru1,6P rate limiting step), PK (PEP to Pyr), PDH (to enter TCA changes pyruvate to acetylcoA)⬦.also minor regulation HK (- by Glu6P)
- steps glycolysis energy produced
- Gly3P to 1,3GlyP (NADH), 1,3GlyP to 3PGly (ATP), PEP to Pyr (ATP)
- steps glycolysis requiring energy
- 1) Glu to Glu6P, 2) Fru6P to F1,6P (at PFK rate limiting step)
- regulation of HK
- inhibited by Glu6P (its product)
- HK v GK
- HK throughout the body, GK only in liver, lower affinity, higher capacity (key to clearing hi concentration glu after meal)
- rate limiting step glycolysis
- Fru6P to Fru1,6P (PFK)
- regulation PFK
- (Fru6P to Fru1,6P); inhibited by ATP and citrate; activated by AMP and Fru2,6P
- regulation of PK
- (PEP to Pyr) inhibited by ATP and alanine, activated by Fru1,6P
- regulation of PDH: phosphorylation state
- (pyr to acetylcoA) active when deP
- cofactors of PDH, specifics and the vitamin they're derived from
- pyroP (thiamine B1), lipoic acid, coA (pantothenate B5), FAD (riboflavin B2), NAD (niacin B3)
- steps urea cycle
- ornithine + carbamoylP to citrulline (+asp) to Arginosuccinate, (-fumarate) to Arginine, (-urea) to ornithine (+carbamoylP) to citrulline
- carbamoyl produced from
- C)2 and NH4 from transamination/deamination
- where difft steps of urea cycle occur
- liver, carbamoyl is in mitochondria, rest in cytoplasm
- purpose Cori cycle
- transfer lactate from RBC and muscle to liver, allowing them to fxn anaerobically
- steps cori cycle
- glu (in mscl or RBC) hydrolyzed to pyr (gain 2ATP), converted to lactate via LDH, lactate taken up by liver converted to pyr by LDH, requires 6ATP to return to glu (in liver)
- endpoints of pyruvate metabolism
- oxaloacetate, alanine, acetyl coA, lactate
- how pyr converted to oxaloacetate
- via pyr carboxylase (w biotin) + ATP
- how pyr converted to lactate? needs?
- via LDH (+NADH)
- how pyr converted to alanine
- via Ala aa trxr
- subunits of electron transport chain
- NADH dehydro, (Q), cyto bcl, cytoC, cytochrome oxidase aa3
- NADH comes in at which step
- NADH dehydro
- FADH2 comes in at which step
- Q
- rotenone blocks
- NADH dehydro to Q (also amylol)
- antimycin A blocks
- cyto bcl to cyto c
- uncoupling of electron transport
- 2,4 DNP
- inhibit transfer to 02
- CN-, N3-, CO
- inihibit ATPase
- oligomycin
- energy NADH produces in electron transport
- 3ATP
- energy FADH2 produces in electron transport
- 2ATP
- how is energy obtained from ketone bodies (what step do they enter metabol?)
- enter as ketoacids as acetylcoA to TCA
- fa syn precursor ____, is converted from ____ of TCA
- fa syn precursor malonylcoA converted from acetylcoA
- regulation of acetylcoA carboxylase
- active when deP (insulin), insulin, citrate. inhibited by glucagon. NOTE: requires biotin
- how is fatty acid use shut off during fa synthesis
- malonylcoA inhibits CAT (carnitine transfer) for txr of fa into mito for beta-oxidation
- what is needed for rxn for desaturation
- need O2, NADPH, cytob5 can insert >9 to COOH end
- why linolenate and lineleate impt
- esstl fa bc only plants can insert dble bonds bw 9 and omega carbon (opp COOH)
- steps of cholesterol syn
- 2 acetylcoA to HMGcoA through HMGCoA reductase (requiring 2NADH) making mevalonate
- HMGCoA reductase: role? requires? regulation?
- cholesterol synthesis, requires 2 NADH and inhibited by cholesterol
- how ketones synthesized
- HMGCoA to acetoacetate (to beta-OHButyrate and back)
- pathway of how ketones be used
- acetoacetate plus succinylcoA go thru thiotrxse and thiolase to TCA
- HMGCoA reductase is found
- NOT in the liver, so liver can't use the ketones it makes
- regulation of glycogen synthase
- when deP (insulin) this is stim in liver and muscle, activated by Glu6P and insulin, inhib by glucagon and epi
-
overall regulation of glyc syn and degradation,
liver v muscle regulation? - glucagon->increase in PKA inhibits gly synthase by P, and activ gly degradation. in liver gly degradation: activated by glucagon and epi, in muscle activated by epi, AMP, and Ca.
- what types links gly synthase form
- alpha 1,4
- how form branches in gly syn
- alpha 1,6 made by glucosyl 4:6 trxase
- how body able to break down TAG in adipose, and its regulation
- hormone sens lipase (+epi, - insulin) breaks into FFA which is carried by albumin, and glycerol which is transferred to liver for gluconeo
- uses of biotin
-
--carboxylation
1) gluconeo (carboxy of pyr in mito)
2) fa syn (carbosy of acetylcoA to form malonyl coA)
3) odd chain fa degradation (propionylcoA to methylmalonylcoA) - signs symptoms biotin defic
- anorexia, (enteritis) N/V, glossitis, alopecia, derm
- causes biotin defic
- egg whites (avidin in egg whites binds biotin avidly), Abx
- retinol
- vit A
- B1
- thiamine
- B2
- riboflavin
- B3
- niacin
- B5
- pantothenate
- B6
- pyridoxine
- pyridoxine
- B6
- pantothenate
- B5
- niacin
- B3
- riboflavin
- B2
- water soluble vitamins
- all B, C, biotin, folate
- common features B defic
- dermatitis, glossitis, diarrhea
- role of pyridoxal P
- amino acid: transamination, decarboxy, deamination
- role of THF
- transfers one carbon units
- signs/symptoms pyridoxal P defic
- convulsion, derm, anemia
- signs/sympt THF defic
- megablastic anemia, neuro
- role B12
- methyl txr THF to homocys to form meth, also methylmal coA to succinylcoA in fa metab (myelination trbl?)
- role of thiamine
- thiamine pyroP: PDH, aKGdehydro, pentoseP (also oxidation of branched aa)
- coenzA: role? requires what vit?
- provides thioesters for acetylcoA, succinyl. Requires pantothenate.
- role pantothenate
- for transferring thioesters (part of CoA), cofactor for acyl txr, and fa synthase complex
- signs/sympt pantothenate defic
- dermatitis, enteritis, alopecia, adrenal insuff (listless, fatigue, burning feet)
- role vitC
- hydroxylation prolyne and lysine for collagen crosslinking, absorb Fe, anti-oxid, cofactor for dopamine to NE
- main causes b12 defic
-
1) no animal products (STRICTEST VEGAN)
2) malabsorb (Sprue, protozoa)
3) no intrinsic factor (pernicious anemia)
4) no terminal ileum (crohns) - b12 nec in what 2 rxns
- form TH4 (to make thymidine to make DNA), homocysteine to methionine
- role vit E, defic causes...
-
antioxidant, defic leads to increased fragility of RBC.
E for Erythrocyte - defic vit A
- night blindness, dry skin, impaired immune response
- excess vit A
- arthralgias, fatigue, HA, skin changes, sore throat, alopecia
- defic in B1, name? clinical presentation?
- (thiamine defic)=Beriberi and Wernicke-Korsakoff. Beriberi: polyneuritis, cardiac, edema. wet beriberi can lead to hi output cardiac failure
- vit B2 defic
- (B2=riboflavin) causes angular stomatitis, Cheilosis, Corneal vascul
- causes of B3 defic
- (B3 defic=pellagra), Hartnup dz, malignant carcinoid syndrome, INH
- B3 defic
- (Pellagra) Diarrhea, dermatitis, dementia, and beefy glossitis
- role B3
- (niacin) for NADH, NADPH.
- thiamine in what specific enz, which is used in which rxns?
- thiamine pyrophosphate, for PDH, aKG, and cofactor for transketolase rxn in HMP shunt
- origin of melanin
-
phenylalanine
(melatonin from tryptophan, both T's) - origin of melatonin
- tryptophan
- what need to make heme
- glycine
- what does tryptophan make
- Niacin (NADH), Serotonin, Melatonin
- what does phenylalanine make
- tyrosine, which makes thyroxine and dopa. dopa makes NE, epi, and melanin
- what does tyrosine make
- thyroxine and dopa. dopa makes NE, epi, and mela
- how NE made
- phenylalanine to tyrosine to dopa to dopamine to NE
- what made by arginine
- creatinine, urea, NO
- histamine comes from
- histidine
- role of B100
-
1) mediates VLDL secretion from liver
2)on VLDL, IDL, LDL so can bind liver - apoA1
- activates LCAT (esterifies 2/3 of plasma cholesterol)
- chylomicron role
- takes dietary tg to tissue, takes dietary chol to liver to make VLDL
- apo B48
- sxn of chylomicron (from intestine)
- apoCII
- cofactor for LPL to work (both chylomicron and VLDL)
- role of apoE, on which molecules for what function
- mediates extra uptake by liver, for chylomicron to make VLDL and for IDL to make LDL send hep chol to tissue
- role LDL
- after VLDL used in tissue LPL, IDL comes back to liver. Hep tg lipase then adds hep chol to IDL to form LDL. So LDL transports hep cholesterol to tissues.
- role IDL
- after tg used out of VLDL comes back to liver to get reloaded with chol to take to tissues.
- role HDL and where come from
- reverse transport of cholesterol to liver. has apoC and apoE. secreted from both liver and intestine.
- energy requiring steps of gluconeo
- ATP for pyr carboxy, GTP for PEPCK
- enzymatic steps different in gluconeo
- 1) pyr carboxylase (pyr to OAA) 2) PEPCK (OAA to PEP) 3) Fru1,6BP (Fru1,6P to Fru6P) 4) glu6P (glu6P to glu). 1,2 replace PK, 3 replaces PFK, 4 replaces GK
- FA synthesis steps mito acetylcoA converted to citrate so enter cytosol.
- acetylcoA + malonylcoA + 2NADPH each cycle, until desired length
- how can glyceral (from TAG) enter gluconeo
- via DHAP/G3P step
- how is gluconeo turned on and glycolysis turned off
- acetyl coA activates pyr carboxy and inactivates PDH (leading pyr to TCA). glucagon P turning off PK. glucagon also decreases Fru2,6BP which inhibits PFK and induce Fru1,6Phosphatase. low glucose inhibits GK. (levels ATP/NADH also influence)
- phosphorylation states insulin v glucagon
- glucagon put on P (via PK), insulin takes off P (via phosphorylase), so with glucagon enz-P, with insulin enz-noP
- phosphorylation states of PFK2
- when PFK2-deP kinase, when PFK2-P phosphatase
- regulation and cofactors pyr carboxylase
- requires biotin and ATP, activated by acetyl coA
- relation of Fru2,6P to PFK activity?
- PFK2 is a kinase when deP (insulin/meal) converting more Fru1P to Fru2,6P, activating PFK1 (increase glycolysis)
- simple way to think of Fru2,6P as regulator?
- fru2,6P hi when lot of reactant (fru1P)
- way to remember irreversible enzymes in gluconeo
- "Pathway produces fresh glu" Pyr carboxy, PEPCK, Fru1,6P, and Glu6P
- what shuttle needed in gluconeo
- Asp/Mal shuttle to get OAA out of mitochondria for PEPCK rxn
- what substrates enter gluconeo
- glucogenic aa, alanine, lactate (Cori cycle). GLUCOGENIC=Met, Thr, Val, Arg, His (+/-Ile, Phe, Trp either gluco or keto). KETO=Leu, Lys and acetoacetate.
- where glu6phosphatase enzyme located
- only liver and kidney, not muscle so muscle can only create glu6 which can't be exported (used glycolysis)
- where malonyl coA from
- product of acetylcoA carboxylase
- 3rd world-baby rapid onset tachycardia, vomit, convulsion
- beri beri, defic B1 due to "polished rice"
- in what clinical condition do you increase niacin, what does it do?
-
IIb combined hyperlipoproteinemia (where both VLDL and LDL are high)
inhibits lipolysis in tissue, decr TAG, decr VLDL which in turn decreases LDL (chol). NET: both TAG and chol decrease. - which of these vitamin defic unusual
- biotin, pantothenate
- when need supplement B6
- INH
- secondary folate defic
- MTX