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Biochemistry II > 22: amino acids, nucleotides, and related molecules > Flashcards

22: amino acids, nucleotides, and related molecules Flashcards

1
Q

how do we use the N in our atmosphere?

A

we can’t use raw N, first has to go through nitrogen fixation and become NH4, which we can use. NH4 is used in amino acids, porphyrin, glutathione, and nucleotides

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2
Q

describe the nitrogen cycle

A

22 pt1 slide 4
key points are nitrifying bacteria that oxidize NH4+ to NO2- (from ox state of -3 to +3) and denitrifying bacteria that reduce NO3- to N2 in atmosphere (ox state of +5 to 0). Nitrogen-fixing bacteria convert N2 into NH4 which other organisms use

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3
Q

how is nitrogen fixed in nature?

A

Nitrogenase complex is the only enzyme that fixes N2. only specific prokaryotes (cyanobacteria and soil bacteria) can do it. Uses ATP to overcome the very stable N2 triple bond (16 ATP and 8 e- and 10 H+ required to fix one N2 to 2 NH4+)

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4
Q

how is nitrogen fixed in industry?

A

Haber process which uses extremely high temps and pressure to overcome the stable N2 triple bond. makes fertilizer

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5
Q

how does nitrogenase complex work?

A

has 4Fe-4S center, 8Fe-7S P cluster, FeMoco , 8 e-, and lots of ATP. reductase subunit and dinitrogenase subunit.. FeMoco is the powerhouse where N is converted to NH3 and is located in the dinitrogenase subunit. the reductase subunit takes electrons from ATP to give to the catalysis reaction
22 pt1 slide 6

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6
Q

nitrogenase complex stoichiometry

A

N2 + 8H+ + 8e- + 16ATP –> 2NH3 + H2 + 16 ADP/Pi

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7
Q

how is ammonia incorporated into biomolecules? next step after N fixing

A

ammonia is incorporated via glutamate and glutamine. Glutamine Synthetase (primary regulation point) converts glutamate + NH4 to glutamine and then glutamate synthase converts Gln and a-KG to 2 Glu–Note this enzyme is not present in animals, instead they get Glu from transamination of a-ketoglutarate during amino acid catabolism or from glutaminase.

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8
Q

how is ammonia transported?

A

in the form of Glu and Gln

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9
Q

how is glutamine synthetase regulated?

A

Allosteric control: products work together to inhibit by concerted inhibition. One individual product only inhibits a little, when all are present a lot of inhibition occurs. allows for finely tuned N flow
Covalent modification: adenylation occurs by adenyltransferase which is modified by UMP causing it to deadenylate glutamine synthetase, making the enzyme active. see 22 pt1 slide 10

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10
Q

review classes of reactions (and their enzymes/cofactors) used in AA and nucleotide biosynthesis

A

transfer of amino groups from Gln (glutamine amiDotransferases)
transfer of amino groups from Glu (glutamate amiNotransferases)
transamination (PLP)
transfer of methyl groups (SAM adds and tetrahydrofolate removes)
phosphorylation (kinase)
dephospho rylation (phosphatase)
add acetyl group (acetylation w acetyl-CoA)
Redox (NADPH/NADP+)
decarboxylation (PLP)

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11
Q

what are glutamine amidotransferases (GATase)?

A

GATase enzymes catalyze transfer of ammonia from Gln to substrate. they have 2 domains, one for Gln and one for the other substrate amino acceptor. The cys nucleophile in the Gln domain is important. There is a channel between domains for the ammonia to transfer, NH3 does not dissociate bc it is toxic!
22 pt1 slide 12

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12
Q

what are glutamate aminotransferases?

A

uses Glu and PLP to perform amino transfer and carboxylation. If Glu and a-KG are present, it’s PLP DEPENDENT. see mech
22 pt1 slide 13

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13
Q

where does the carbon skeleton for amino acid biosynthesis come from?

A

bacteria: synthesize all 20
mammals: synthesize half, the rest are form diet
derived from intermediates of glycolysis (3-phosphoglycerate, PEP, pyruvate), CAC (a-ketoglutarate, oxaloacetate), and pentose phosphate pathway (ribose 5 phosphate, erythrose 4-phosphate).

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14
Q

review carbon flow in the pentose phosphate pathway

A

key points are ribose-5-phosphate that comes from glucose 6-phosphate (glycolysis) and erythrose 4-phosphate that comes from fructose 6-phosphate and glyceraldehyde 3-phosphate (glycolysis)
22 pt1 slide 15

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15
Q

what’s the deal with selenocysteine? draw it and know its synthesis

A

the 21st amino acid, human genome contains 25 selenoprotein-coding genes. same structure as Cysteine but with Se instead of S.
biosynthesis: occurs attached to tRNA. Serine is loaded to tRNA then modified with phosphate and then Selinium, creating Selenocysteine (Sec)
22 pt1 slide 16

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16
Q

amino acids made from glycolysis intermediates

A

3-phosphoglycerate: Ser, Gly, Cys
PEP: Trp, Phe, Tyr
pyruvate: Ala, Val, Leu, Iso

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17
Q

amino acids made from CAC intermediates

A

a-ketoglutarate: Glu, Gln, Pro, Arg

oxaloacetate: Asp, Asn, Met, Thr, Lys

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18
Q

amino acids made from PPP intermediates

A

ribose 5-phosphate: His

erythrose 4-phosphate: Trp, Phe, Tyr

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19
Q

what is PRPP?

A

a heavily used intermediate in AA and nucleotide synthesis. made from ribulose 5-phosphate (PPP) and ATP using ribose phosphate pyrophosphokinase. PRPP is directly used to make Trp and His
structure 22 pt1 slide 18

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20
Q

How is Cys made in humans

A

No de nove synthesis for Cys, so a transsulfuration cycle links Cys, Met, and SAM. Met is adenylate to make SAM then methyl is removed to make S-adenosylhomocystein. This reacts with water and serine and water and eventually ends up with cysteine
mech 22 pt1 slide 20

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21
Q

how are ringed AAs made?

A

using PEP and erythrose 4-phosphate. PRPP is used for Trp and all go through chorismate intermediate
22 pt1 slide 22

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22
Q

how is His made?

A

from ribose 5-phosphate using PRPP, ATP, and Gln. Note that ATP is not used as a cofactor here but as a metabolite, forming a complex with PRPP but maintaining all its phosphates.

23
Q

how is amino acid synthesis regulated?

A

allosteric regulation: end products affect the activity of the first reaction (glutamine synthetase for example). can be simple feedback inhibition or complex concerted inhibition
also regulates by sequential feedback inhibition and enzyme multiplicity where multiple isoenzymes catalyze the same step, but each is controlled by different modulators. The pathway can’t be shut down by just one modulator, allows for fine tuning mechanism
22 pt1 slide 25-26

24
Q

what is porphyrin? what are some examples?

A

Porphyrins are large 4 ringed molecules.
Hemes-containing proteins w central iron metal. have structural function as hemoglobin and catalytic function as P450 (mixed function oxidase) cytochromes.
Chlorophylls have magnesium central metal. function as part of LHC and special pair in PSI and PSII

25
Q

what are porphyrins made of?

A

glycine converts to delta-aminolevulinate and goes through series of reactions to make protoporphyrin

26
Q

how is d-aminolevulinate biosynthesized from glycine?

A

22 pt2 slide 3
succinylcholine-CoA and glycine react in ALA synthase to make a-amino-B-ketoadipate with then converts to d-aminolevulinate by ALA synthase again. Releases CoA-SH and CO2. This is different for bacteria/plants but don’t need to know that mech

27
Q

how is heme biosynthesized?

A

22 pt2 slide 4
takes 8 d-aminolevulinate and water to make 4 porphobilinogen. 4 of those combine and blah blah blah wee make protoporphyrin which has Fe2+ added to make Heme. 2 lead sensitive steps, the first step and the last step. Note that Fe2+ is inserted by enzymes because free metals are toxic and must be contained

28
Q

what are porphorias?

A

genetic diseases with defects in enzymes of the porphyrin biosynthetic pathway. can result in red uric, fluorescent teeth, sun sensitive skin, and anemia. vampires

29
Q

how is bile synthesized?

A

bile is made from heme that goes through heme oxygenase and releases CO and Fe2+ (these are toxic, ferritin binds Fe2+ and CO likely has a signaling role) producing biliverdin-which is green. biliverdin is reduced to bilirubin - which is yellow - and then further modified to urobilin and stercobilin which are excreted in urine. (bilirubin is present in bile)

30
Q

how does bile biosynthesis relate to jaundice and bruises?

A

impaired liver function or blocked bile secretion causes bilirubin to leak into the blood stream. recall that bilirubin is yellow, so it gives skin a yellow color in the blood stream. infant jaundice is due to lack of glucuronyl-bilirubin transferase, which catalyzes transfer of blood bilirubin to the intestine.
bruises are due to erythrocytes breaking, releasing here which is then broken down. Bruises are often green first (biliverdin) and then yellow (bilirubin)

31
Q

how is glutathione synthesized? draw structure of glutathione

A

glutamate and cysteine react (using ATP) to make y-glu-cys. Glycine is added and another ATP to make glutathione. uses enzymes y-glutamyl cysteine synthetase and glutathione synthetase
22 pt2 slide 8

32
Q

why is glutathione important?

A

oxidized and reduced forms are important redox buffers. it has Cys-SH group it can donate electrons with to repair oxidative damage of enzymes

33
Q

describe the relationship between ROS, GSH, and disease

A

reactive oxygen species (ROS) are produced in reactions and systems are in place to deal with normal levels, but too much ROS is very bad. They cause oxidative stress which increases with age and increase disease states. GSH is used to alleviate effects of ROS by directly converted ROS or fishing protein damage.
22 pt2 slide 10

34
Q

what is the role of nitric oxide synthase?

A

synthesizes NO’ radical from arginine. NO’ is toxic, but is also an essential signaling molecule that causes vasodilation. too much NO’ causes sepsis, no blood pressure. too little NO’ causes heart disease and high blood pressure

35
Q

what are the classes of biological amines?

A

neurotransmitters (you know what those are) and polyamines (complex with DNA, such as spermidine required in large amounts in dividing cells)

36
Q

PLP is used for what type of reactions? what’s the mech and can you figure out products/reactants when shown one?

A

22 pt2 slide 35

used in aminotransferase reactions as a decarboxylation cofactor

37
Q

how is histamine formed? what is histamine used for?

A

histidine undergoes PLP dependent decarboxylation. histamine is a vasodilator, released during allergic response and stimulates acid secretion in stomach.
cimetidine (Tagamet) is a pharmaceutical based on histidine
22 pt2 slide 14

38
Q

how is dopamine formed?

A

tyrosine is hydroxylated by tetrahydrobiopterin cofactor to make Dopa. Dopa is decarboxylated (PLP) to make dopamine
22 pt2 slide 15

39
Q

how is epinephrine made?

A

dopamine is hydroxylated to form norepinephrine, then SAM adds methyl group to form epinephrine
22 pt2 slide 16

40
Q

mechanism of polyamine biosynthesis

A

ornithine reacts with PLP, produces ornithine decarboxylase (Schiff base) intermediate with the two molecules linked together. then releases CO2 as PLP is regenerated and putrescine is formed. Putrescine is precursor to polyamines

41
Q

what are nucleotides used for?

A

precursors to DNA/RNA
components of cofactors eg NAD, SAM, CoA
components of biosynthetic intermediates eg UDP-glucose (makes sucrose), ADP-glucose (makes starch)

42
Q

draw the nucleotide bases

A

22 pt2 slide 19

43
Q

nucleoside vs nucleotide

A

nucleoside: base and sugar
nucleotide: base and sugar and phosphate

44
Q

how are nucleotides synthesized de novo?

A

22 pt2 slide 21
Purines: starts with ribose in PRPP, amino acid pieces are added to build up base to IMP (branch point). IMP converts to AMP or GMP. those each convert to ADP/ATP and GDP/GTP respectively
pyrimidines: aspartate converts to Orotate, PRPP is added and UMP is formed. UMP converts to UDP/UTP and then CTP

45
Q

how are nucleotides synthesized salvage pathway?

A

22 pt2 slide 21

purines: adenine and guanine are salvaged, reacted with PRPP to make adenosine and guanosine which make AMP/GMP and so on to ATP/GTP
pyrimidines: uracil is salvaged to uridine to UMP which converts to UDP/UTP then CTP. cytosine is savaged to cytidine and converted to CTP

46
Q

how is purine biosynthesis regulated?

A

feedback inhibition. first step (PRPP synthetase) is inhibited by end product ADP. concerted inhibition occur at second step, glutamine-PRPP amidotransferase with AMP, GMP, and IMP all inhibiting. there is also product inhibition of each individual purine after the IMP branch point
22 pt2 slide 22

47
Q

how are nucleoside monophosphate converted to triphosphates?

A

adenylate kinase uses ATP to phosphorylate ADP, forming 2 ADP which go through oxidative phosphorylation or glycolytic enzymes to make ATP.
other nucleosides are similar, ATP donates phosphate group via nucleoside monophosphate kinase (each is specific to a base!) and makes NDP. then a Non specific nucleoside diphosphate kinase converts NDP to NTP by using another NTP to give phosphate group
22 pt2 slide 23

48
Q

how are deoxyribonucleotides formed?

A

ribonucleotide reductase, the only enzyme to do this. catalyzes reduction of the 2’ ribose carbon. ONLY diphosphate ribonucleotides are substrates. the enzyme is reduced and must be reset by glutaredoxin and thioredoxin.
22 pt2 slide 24

49
Q

how is ribonucleotide reductase regulated?

A

specificity for each of the 4 substrates is regulated for via the substrate specificity site. When [dGTP] is high, it binds to this site and decreases affinity for GTP bc no more is needed. the enzyme is allosterically regulated at a primary regulation site, eg ATP binds and promotes activity, dATP binds and inhibits activity.

50
Q

describe the unique structure of ribonucleotide reductase

A

22 pt2 slide 25
R1 subunit: has regulatory sites and thiol residues
R2 subunit: has stable tyrosine radicals that catalyze the reaction

51
Q

mechanism of ribonucleotide reductase (don’t need to know actual electron pushing)

A

22 pt2 side 26
first a radical is created on the 3’ c of the sugar via the Tyr radical. then 2’ is protonated and dehydrated leaving cation. carbocation is stabilized by the radical, then protonated by SH. the radical 3’ abstracts proton from enzyme, leaving the enzyme with a Tyr radical and a disulfide bond which is reset via glutareddoxin.

52
Q

How is thymidylate derived?

A

NOT from ribonucleotide reductase. dTMP comes from dCDP and dUMP reacting in the enzyme thymidylate synthase. Also, the de novo pathway to dTMP only involves deoxyribonucletides, not ribonucleotides
thymidylate synthase uses tetrahydrofolate which must be recycled between N5,N10-methylene-tetrahydrofolate and 7.8 dihydrofolate. the recycling uses serine and PLP!
22 pt2 slide 32

53
Q

how do chemotherapeutics work?

A

cancer cells have uncontrolled division and a greater need for DNA and RNA precursors, so inhibiting nucleotide biosynthesis can limit them. targeting glutamine amidotransferases can help as they are N donors in several nucleotide biosynthesis. Another target is thymidylate synthase and dihydrofolate reductase as part of the biosynthesis for dTMP

Biochemistry II (13 decks)

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