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MBB266 > Staniforth (Biosynthesis and metabolism) > Flashcards

Staniforth (Biosynthesis and metabolism) Flashcards

1
Q

Why did evo of CO2 (decarboxylation) give strong thermodynamic pull to reactions?

A
  • v stable
  • easily escapes site of reaction (as gas/soluble bicarb)
  • more products than reactants (-ΔG)
    (R-COOH RH + CO2)
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2
Q

How does carbon enter metabolism?

A
  • photosynthesis
  • carboxylations
    eg. pyruvate + CO2 –> oxaloacetate
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3
Q

How does hydrogen enter metabolism?

A
  • H2O
  • NH4
  • H2 (g)
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4
Q

How does oxygen enter metabolism?

A
  • H2O
  • CO2
  • molecular oxygen reactions
  • Phe + O2 –> Tyr (+ΔG)
    = biosynthetic reaction as uses NADPH, not NADP
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5
Q

Where is S found in cell?

A
  • SH = high energy thioesters
  • Fe-S proteins = redox centres
  • SH groups important for protein folding
  • energy store
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6
Q

Why is acetyl CoA high energy?

A
  • great bond donor and easily separated to donate CoA group
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7
Q

Why are S proteins so common?

A
  • pyrites used in primitive Earth instead of NADH –> NAD+
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8
Q

How does S enter metabolism?

A
  • MOs/plants get from H2S

- higher organisms get from diet, eg. Met

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9
Q

What are the advantages of using S?

A
  • S-S bonds strong but form and break under mild conditions (so more flexible)
  • S binds to Fe
  • thioesters have less resonance stabilisation than O esters –> carry more G
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10
Q

How is Ser used to get Cys?

A
  • Ser activated by acetyl CoA

- captures S from H2S to give Cys

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11
Q

How does nitrogen enter metabolism?

A
  • N2 (g) v stable = N fixation by nitrogenase
  • NH3 quite stable = by glutamate deHase
  • glutamate synthase
  • glutamine synthetase
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12
Q

What is the importance of nitrogen in metabolism?

A
  • forms H bonds and Schiff base links
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13
Q

How does P enter metabolism?

A
  • naturally oxidises to phosphate under atmospheric conditions
  • phosphate used directly by cell
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14
Q

What is the difference between 1° and 2°metabolic pathways?

A

1°

  • basic housekeeping functions
  • in essentially all cells
  • largely constitutive

2°

  • specialised functions
  • in all differentiated cells
  • inducible
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15
Q

What are the functions of glycolysis?

A
  • ATP and NADH prod

- intermediates for biosynthesis

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16
Q

What is the location of glycolysis?

A
  • cytosol
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17
Q

What is the overall reaction of glycolysis and pentose phosphate pathway?

A
  • glucose –> pyruvate
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18
Q

When is glycolysis used, and when is phosphate pentose pathway used?

A
  • glycolysis if cell needs energy

- PPP if cell needs biosynthesis

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19
Q

What are the functions of pentose phosphate pathway?

A
  • gen C5 sugars and NADPH for biosynthesis
  • breakdown route for C5 sugars
  • other intermediates for biosynthesis
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20
Q

What is the location of pentose phosphate pathway?

A
  • cytosol
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21
Q

What is the overall reaction of Link Reaction?

A
  • pyruvate —-pyruvate deHase—> acetyl CoA + CO2 + NADH
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22
Q

Is Link reaction favourable, and why?

A
  • v favourable

- decarboxylation

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23
Q

What are the functions of the Link Reaction?

A
  • processes pyruvate for KC
  • source of acetyl CoA
  • NADH prod
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24
Q

What is the location of the Link Reaction?

A
  • mito
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25
Q

How Krebs Cycle discovered to be a cycle?

A
  • measured resp in muscle tissues
  • added succinate and lots more C prod than what was added
  • ∴ cycle w/ catalytic property
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26
Q

What are the functions of Krebs Cycle?

A
  • NADH and GTP prod

- gen intermediates for biosynthesis

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27
Q

What is the location of the Krebs Cycle?

A
  • mito
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28
Q

How does ATP prod by Krebs Cycle compare to glycolysis?

A
  • 24 v 2
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29
Q

What is a top up (anaplerotic mechanism) for Krebs Cycle?

A
  • pyruvate + CO2 + ATP + H2O –> oxaloacetate + ADP
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30
Q

Why is a cycle a good design for a precursor supply system?

A
  • extra supply of any intermediate can top up cycle
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31
Q

What are the functions of mito e- transport system?

A
  • gen ATP (via NADH and FADH2) and GTP

- maintaining redox balance (NADH–>NAD+)

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32
Q

What reaction occurs during β-ox of FAs?

A
  • FAs –> acetyl CoA

- NADH and FADH2 prod

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33
Q

What are the functions of β-ox of FAs?

A
  • extracting energy from lipid stores

- gen 2C units for biosynthesis

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34
Q

What is gluconeogenesis?

A
  • opp of glycolysis

- biosynthesis of sugars from non-carb prescursors

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35
Q

What is the overall reaction of gluconeogenesis?

A
  • pyruvate, AAs –> sugar
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36
Q

What is the function of gluconeogenesis?

A
  • sugar supply when glucose scarce
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37
Q

What are the locations of gluconeogenesis?

A
  • mito and cytosol

- mainly liver, some in kidney

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38
Q

What are the 3 methods for control of biosynthetic pathways?

A
  • isoenzymes
  • single enzyme cumulative control
  • single enzyme concerted control
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39
Q

How can isoenzymes be used to control biosynthetic pathways?

A
  • several enzymes doing same job, w/ small diff, so 1 can be inactivated but not others
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40
Q

What is an example of a pathway using isoenzymes?

A
  • amino acid biosynthesis
  • 3 diff asportkinases in E. Coli for conversion of aspartic acid to aspartyl phosphate
  • same aspartokinase domain, but slightly diff regulatory domain
  • 1 is not inhibited, 1 inhibited by Thr and 1 inhibited by Lys
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41
Q

How can a single enzyme with cumulative control be used to control biosynthetic pathways?

A
  • eg. glutamine synthetase
  • 1 product has inhibitory activity
  • next has more until enzyme totally inhibited
  • DIAGRAM*
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42
Q

How can a single enzyme with concerted control be used to control biosynthetic pathways?

A
  • eg. lysine biosynthesis
  • each product alone has no inhibitory activity
  • combo of products gives inhibitory activity
  • DIAGRAM*
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43
Q

What is the rate determining step?

A
  • slowest step
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44
Q

What is the committed step?

A
  • means reaction continues
  • relax control and get end product
  • don’t if heighten it
  • not necessarily slowest
45
Q

Why is distributive control of pathways a poss?

A
  • prob over simplification to say cellular control of pathways occurs directly by variations in rate of indiv enzymes
46
Q

What is the distributive control hypothesis?

A
  • flux through a pathway is a system property rather than simply property of indiv control enzymes
47
Q

What is flux?

A
  • no. molecules being transformed per unit time

- not equal to conc

48
Q

What is the equation to calc flux coefficient (C)?

A
  • (steady state flux/steady state flux) / [enz]/[enz]
49
Q

What diff values of flux coefficient (C) do enzymes have at diff points in pathway, and what does this contradict?

A
  • early enzymes have low C values
  • later enzymes have high C values
  • contradicts traditional role of allosteric control
50
Q

How do you do metabolic flux analysis?

A
  • identify enzymes involved in pathway
  • map levels of as many intermediates as poss (‘metabolome’)
  • investigate effect of increase or decrease in amount/activity of specific enzymes
  • work out contribution of each enzyme to overall flux
51
Q

What is the metabolome?

A
  • quantitative complement of all low mol weight molecules present in cell under given conditions
52
Q

What is the greatest implication of distributive control hypothesis?

A
  • for biotechnologists

- need to decide which enzymes to increase/improve to result in enhanced yields of useful products

53
Q

In the pathway

A —enz 1–> B —enz 2–> C —enz 3–> D

what effect would increasing levels of enz 2 have?

A
  • increase rate of B –> C
  • decrease B
  • increase C
  • not as high and as an immediate effect as would expect, as enz 1 and 3 still have impact
54
Q

How do you increase flux through pathway?

A
  • increase amount of single enzyme rarely increases flux
  • increasing several enzymes does
  • nature usually increases all enzymes in pathway, eg. lac operon
55
Q

Is pathway of biosynthesis distinct from pathway of degradation?

A
  • usually
56
Q

What is the basic principle of group carriers/donors?

A
  • DIAGRAM*
  • molecule of B loaded onto carrier and activates it
  • carriers energetically unstable when loaded so -ΔG to donate group
  • loading generally req energy
57
Q

What are the major group carriers for biosynthesis?

A
  • C1 = tetrahydrofolate
  • C1-methyl = s-methyladenosine
  • C1-carboxyl = biotin
  • C2 = acetyl CoA
  • C3 = PEP
  • C5 = isopentenyl pyrophosphate
  • amino = Gln/Glu
  • sulfur = Cys
  • sugar = nucleosidediphosphates
  • complex (eg. C-C-N) = eg. Gly
58
Q

Why is biotin a good carrier molecule?

A
  • preferable for CO2 to leave as lots of Os close together
59
Q

How does biotin donate its COO group?

A
  • ATP + bicarb –> carboxyphosphate

- carboxyphosphate wants to lose phosphate, cat addition of COO group to biotin (forms carboxybiotin enzyme)

60
Q

What is an example of COO addition via biotin?

A
  • pyruvate –> oxaloacetate
  • cat by pyruvate carboxylase
  • biotin-COOH donates COOH
  • KC anaplerotic reaction
61
Q

What group does tetrahydrofolate contains many copies of?

A
  • Glu
62
Q

Can C1 be carried in a variety of oxidation states?

A
  • yes
63
Q

What is the role of FH4 in the biosynthesis of dTMP?

A
  • donates methyl group (unusual)
  • during donation, FH4 converted to FH2
  • NADPH needed to reconvert FH4 (energy input)
  • ultimate source of methyl group is Ser
64
Q

What is the most common methyl group carrier?

A
  • S-adenosyl methionine (SAM)
65
Q

How does SAM donate its methyl group?

A
  • activation req ATP
  • CH3 activated by S+
  • Ser ultimate source of methyl groups (via FH4)
66
Q

Why is methyl group on SAM a good leaving group?

A
  • S+ next to it tries to grab e-s
67
Q

What is the outline of SAM structure?

A
  • S+ w/ single bond to adenosine, CH3 and Met
68
Q

What is an example of C2 donation?

A
  • FA biosynthesis
69
Q

Why does phosphoenolpyruvate have no carrier (C3 units)?

A
  • in built energy source
70
Q

Why is phosphoenolpyruvate (C3) a good donor?

A
  • -ve groups attached to each other

- not good sterically so -ΔG to get rid of repulsion

71
Q

How does isopentenyl pyrophosphate donate C5 group?

A
  • mevalonic acid made up of 3 acetyl CoAs
  • CO2 lost forming IPP, pulls reaction forward
  • IPP v reactive, has high free energy of reaction
  • reactions occur leading to highly reactive carbonium ion
72
Q

How are NH2 groups donated?

A
  • Gln –> Glu +NH2
  • uses ATP
  • no activated carrier
  • only R group NH2 donated
73
Q

What various types of C1 unit can be carried on FH4?

A
  • methanol (CH3-OH)
  • formaldehyde (H2C=O)
  • formic acid (OH-HC=O)
74
Q

What is the diff between purine and pyrimidine skeletons?

A
  • purine 2 ring

* DIAGRAMS*

75
Q

What is phosphoribosyl pyrophosphate important for?

A
  • allosteric control and end product inhibition as control of biosynthesis often involves 1st/2nd step
76
Q

What is phosphoribosyl pyrophosphate?

A
  • high active form of ribose
77
Q

What are the 2 phases of purine biosynthesis?

A
  • activation of O by phosphorylation

- nucleophile attacks activated C

78
Q

What kind of donor can Asp function as?

A
  • NH2
79
Q

What are the origin of all atoms in purine skeleton?

A
  • N from Asp
  • N from Gln
  • NH from Gln
  • CCN from Gly
  • 2x CH from FH4
  • CH from CO2
80
Q

What is the core pathway in purine biosynthesis?

A
  • ribose-5-P –> PRPP –> phosphoribosylamine –> IMP
81
Q

What are the processing reactions in purine biosynthesis?

A
  • IMP –> AMP

- IMP –> GMP

82
Q

Why is GTP used in processing of IMP to other nucleotides?

A
  • if making ATP, makes sense to use diff nt in its biosynthesis
83
Q

Why is deoxyribose wanted in DNA instead of ribose?

A
  • more stable

- so can survive longer than RNA

84
Q

What is the overall control of purine nt biosynthesis?

A
  • overall control/end product feedback
  • balancing levels of ATP/GTP
  • balancing levels of purines/pyrimidines
  • balancing levels ribose vs deoxyribose
  • not clear if cumulative or concerted but def not isoenzymes
85
Q

Why is control of purine nt biosynthesis necessary?

A
  • avoid wastage and holding anything back
86
Q

How is the biosynthesis of purine nts balanced?

A
  • end products (ATP/GTP) are co-reactants in opp branch for conversion of IMP
87
Q

What is tetrahydrofolate used for, and why does it have such serious side effects?

A
  • widely used drug in chemo

- side effects as affects DNA and RNA synthesis

88
Q

What is Ki, and what do the values mean?

A
  • inhibition constant = how tightly enzyme bound

- <1 means need hardly any and it binds, so good comp inhibitor

89
Q

How can fluorouracil and methotrexate be used in cancer chemo?

A
  • fluorouracil = fluorinated analog of dUMP, inhibitor
  • only works w/ pyrimidine nts (not purine analogs)
  • ring assembled, then ribose-P attached
  • methotrexate kills all rapidly dividing cells (inc bone marrow, hair follicles) –> Ki < 1nM
90
Q

How is chirality of Cα established?

A
  • transamination reaction using pyridoxal phosphate
91
Q

What are the 3 enzymes of amination?

A
  • glutamate deHase
  • glutamate synthase
  • glutamine synthetase
92
Q

Why is double bond formation important in AA formation?

A
  • prevents rotation –> planar
93
Q

What is Schiff base formation?

A
  • NH2 + -CHO
94
Q

Why is Schiff base formation important in establishing chirality?

A
  • geometry of enzyme ensures H+ added from specific side
95
Q

What are the metabolic families of AAs?

need to know 1 eg.

A
  • oxaloacetate
  • PEP
  • ribose-5-P
  • pyruvate
  • 3-phosphoglycerate
  • α-ketoglutarate
96
Q

How are AAs classified into families?

A
  • according to their biosynthetic precursor
97
Q

What are the general principles of AA biosynthesis?

A
  • intermediate of glycolysis/PPP/KC –> req side chain assembled on α-keto acid –> NH2 group added by transamination
98
Q

What is the mechanism of glutamate deHase?

A

Transamination:

1) binding of PLP to enzyme
- binds reversibly
2) exchange
- Schiff base formation is reversible
3) transfer of -NH2 to PLP
- addition of water
4) 2nd substrate
- loss of water
- Schiff base formed
5) Schiff base linkage exchange w/ enzyme
- AA has effectively exchanged R group

99
Q

How is transamination poss?

A
  • exchange of amino groups freely reversible
  • AAs form “pool” to freely interchange
  • similar amount of each AA until 1 req
  • not great for control, but good for supply
100
Q

What are the contrasting roles of Glu and Gln in biosynthesis of NH2 containing molecules?

A
  • Glu has COOH / Gln has CONH2
  • α-amino group of most AAs from Glu
  • Gln major donor of NH2 groups in biosynthesis
101
Q

How is Ser biosynthesised?

A
  • from 3-phosphoglycerate

- req NAD, Glu and H2O

102
Q

How does KM control amination?

A
  • α-oxoglutarate –> glutamate
  • high KM at high [NH3] = use of NH3 and NADH
  • low KM at low [NH3] = use of NH3, ATP and NADPH
103
Q

What method of pathway control is used for end product inhibition on glutamine synthetase?

A
  • cumulative inhibition
104
Q

What are the 2 forms of glutamine synthetase interconverted at adenylyl transferase, in the control of glutamine synthetase?

A
  • DIAGRAM*
  • ATP used to add AMP group
  • adenylyl transferase has dual specificity, specifically changed by protein
105
Q

What are the 2 forms of P protein in the control of glutamine synthetase?

A
  • adenylating form deadenylating form (addition of UMP)
  • cat by uridyl transferase
  • reverse reaction spontaneous
106
Q

What is the role of deadenylating form of P protein?

A
  • turns glutamine synthetase back to active form
107
Q

How is uridyl transferase under allosteric control?

A
  • glutamine –> uridyl transferase
108
Q

What is the significance of control of uridyl transferase?

A
  • reaction important threshold in N reactions, so has stringent control
  • mini amplification cascade?

MBB266 (7 decks)

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