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biological chemistry 2 > biosynthesis of natural products > Flashcards

biosynthesis of natural products Flashcards

1
Q

natural product

A

a chemical compound produced by an organism that plays a crucial role in biological processes

can have primary and secondary metabolites

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2
Q

primary metabolites

A

directly involved with growth, essential for life and are universal across organisms

amino acids, nucleic acids, proteins, carbs ect….

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3
Q

secondary metabolites

A

not directly involved in growth, plays other roles for advantages, diverse functions, SPECIES SPECIFIC

alkaloids, terpenes, fatty acid derived substances, polypeptides

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4
Q

alkaloids

A

come from amino acids, contain nitrogen atoms and are significant for pharmacological effects

basic (alkaline) properties, have heterocyclic rings, soluble in water and organic solvents which make them easy to extract and are biologically active

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5
Q

classification of alkaloids

A

true alkaloids - from plants - nitrogen atom in heterocyclic ring

proto alkaloids - from animals - nitrogen atom with no cyclin structure

pseudo alkaloid - from microbes - not derived from AA but still have nitrogen atom

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6
Q

phosphate transfer

A

used because the transfer of phosphate has a negative free gibbs energy which drives reactions

Delta G = Delta G0 + RTln(conc of products/ conc of reactants

phosphate hydrolysis is a spontaneous reaction

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7
Q

leaving group and resonance of ATP

A

nucleophilic attack on the last phosphate

easy to transfer as ADP is a stable leaving group as resonance structure is stable

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8
Q

metals and ATP

A

a metal ion is required by all ATP utilising enzymes as their increases electrophilicity of phosphorous to stabilise leaving group - making it easier

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9
Q

acetyl CoA

A

a central metabolite with a SH group and COCH3 (COA), used in a range of reactions such as citric acid cycle, fatty acid synthesis

specifically focusing on fatty acid synthesis, start with an acetyl CoA to elongate with a series of reactions to make a FA

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10
Q

thioster in acetyl CoA

A

thirster hydrolysis is much easier than ester hydrolysis as have a large -ve value

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11
Q

acetyl coa formation by fatty acid oxidation

A

beta oxidation pathway converts FA to acetyl coa

forwards and backwards reactions are quite similar

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12
Q

acetyl coa from acetate

A

this reaction is energeritically unfavourable - not spontaneous so ATP coupled reactions to make this reaction possible

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13
Q

importance of fatty acids

A

can be used as a new energy source

antibiotic resistance

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14
Q

fatty acid synthesis

A

this uses the biological claisen condensation reaction

  • acetyl coa is used as a source of both nucleophile and electrophile
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15
Q

type 1 fatty acid synthase

A

big structure, multi-domain complex which is covalently bound, very efficient

common to both mammals and fungi

Animal FAS enzyme has two alpha homodimers
fungal FAS has 6 alpha 6 beta dodecamers

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16
Q

type 2 FAS

A

individual enzymes instead of one big one, each enzyme catalyses a single step “specialise workshops’

  • found in archaeological and bacteria
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17
Q

step 1 acetyl - acp formation

A

ACP synthase converts ACP-OH –> ACP-SH

nucleophilic addition of ACP-SH onto acetyl coa, elimates COASH forming acetyl ACP

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18
Q

ACP

A

scaffold protein acts as a carrier for the growing fatty acid chain

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19
Q

step 2 - ketosynthase - acetyl synthase formation

A

nucleophilic addition of synthase enzyme
elimination of S-ACP
forming acetyl synthase

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20
Q

step 1 and step 2

A

this is one side of the reaction

these two steps form the electrophile for c-c forming reaction in step 5

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21
Q

step 3 - malonyl COA synthesis by ACC

A

malonyl deprontates acetyl coa to form enolate to act as a nucleophile for nucleotides addition to carboxybiotin

elimination of biotin to form malignly coa

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22
Q

why malonyl coa

A

undergoes easy loss of co2

23
Q

step 4

A

nucleophilic addition of base from MAT enzyme to malonyl coa

elimination of SCOA so malonyl is now bound to MAT

nuc addition of ACP-SH, elimination of MAT to form malonyl -ACP

24
Q

MAT enzyme

A

32kD monomer with 2 subdomains with a conserved active site between different organisms

25
Q

getting ready for step 5

A

step 1 + 2 produced acetyl synthase - electrophile
step 3 + 4 produced malonyl ACP = nucleophile

now the c-c bond forming reaction can begin - claisen condensation

26
Q

step 5

A

decarboxylation of malonyl -acp to form enolate

nuc addition of enolate to acetyl synthase forming new c-c

elimination of synthase c-s cleavage and acetoacetyl acp is formed

27
Q

step 5 KS enzyme

A

uses ketoacyl synthase enzyme to form c-c

important in transacetylation - the transfer of acetyl group from one molecule to another
1- acetyl donor
2 nucleophilic attack
3 form product acetylated

28
Q

step 6

A

acetoacetyl acp reduced by KR to go from ketone to alcohol to form beta hydroxy butyryrl acp

29
Q

KR step 6 enzyme

A

ketoreducatase - reduction of ketones using NADPH as hydride source
proton comes from active site Tyr - OH residue

if this reduction doesnt occur then unsaturated fatty acid forms

30
Q

step 7

A

dehydration using E2 mechanism, deportation of step 6 product to form c=c , loss of OH as water

beta hydroxy becomes crotonyl-acp

31
Q

step 8

A

alkene reduction of crotonyl acp to butyric-acp using nadph using ER - enoyl reducatase

32
Q

step 9

A

elongation

repeating steps 5-8 over and over again to increase chain length via claisen condensation
each time growing by 2 carbons

KR , DH, ER

33
Q

step 10

A

termination - chain termination step

hydroylsis reaction catalysed by various thioesterases to get rid of the thioester

34
Q

polyketides

A

natural secondary metabolite

active against microorganisms due to their ability to inhibit essential primary metabolic processes = defence mechanism

35
Q

examples of polyketides

A

streptomycin - antibiotic

doxorubicin - anti cancer

erythromycin A - antibiotic

36
Q

polyketide synthesis

A

not biosynthesised by humans, only microorganisms

3 key differences to fatty acid synthesis

  1. a greater variety of starter units
  2. a greater variety of extender units
  3. non functional or missing KR DH ER enzymes
37
Q

oxygen atoms in polyketides

A

compared to FA., have more number of oxygen atoms and much wider variety in structure

38
Q

polyketide synthases

A

PKs - evolutionarily and mechanistically related to FASs

they catalyse the step-wise elongation of polyketide chain and functional group modifications

39
Q

3 types of PKs

A

based on enzyme architectures and catalytic mechanisms

categorised as iterative or non iterative based on whether they catalyse multiple rounds of elongation

40
Q

type 1 pks bacterial

A

non interactive and highly modular

mode of substrate activation - ACP

typical product - reduced

41
Q

type 1 pks fungal

A

iterative and single module

mode of substrate activation - ACP

typical product - aromatic and reduced

42
Q

type 2 pks

A

iterative and discrete enzymes

MOS activation - ACP

typical product = aromatic

43
Q

type 3 PKS

A

iterative

MOS activation - CoA

typical product - aromatic

44
Q

type 1 PKS case study

A

DEBS biosynthesis

involved series of chain elongation and modifications - ring closes

45
Q

ketoreductases in PKS

A

consist of structural and catalytic domains that bind to NADPH

46
Q

DEBS biosynthesis - DEBS 1 - load, mod 1, mod 2

A
  1. loading, load start unit onto ACP
  2. chain elongation move starter unit onto ketosynthase - acp picks up extended unit (nucleophile) CO2 loss
  3. epimerisation and reduction - reduced by nadph, inversion of configuration
47
Q

DEBS 2 - mod 3 mod 4

A

M3 lacks KR domain so no reduction, product contains ketone group

m4 - identical to FAS

48
Q

DEBS 3 - mod 5 mod 6 end

A

mod 5 mod 6 reactions similar to those in step 1 in FAS - similar to clasien

termination - cyclic mechanism

acp transfered and becomes ester, then cyclisation to close ring = cyclic ring

49
Q

type 3 PKS case study

A

chalcone synthesis

  • uses a single KS like active site to catalyse the repetitive condensation of acetate to a CoA starter molecule

chain extension intramolecular condensation and aromatisation of liner intermediate

uses claisen condensation so is similar to FAS

50
Q

isoprenoids / terpenoids

A

all contain multiple of 5 carbons and are biosynthetic ally derived from five carbon isopentenyl units

contain oxygen

used for a wide range - anticancer, malaria, inflammation

51
Q

isoprenoids biosynthesis - hemiterpenes (5 carbon molecules)

A

DMAPP is an electrophile used in this synthesis, readily form a carbocation

IPP is a nucleophile used, markonikov addition of an electrophile to a C=C bond

involves two pathways
1. mevalonate pathway
2. MEP pathway

52
Q

mevalonate pathway

A

Mevalonate Conversion: undergoes phosphorylation and decarboxylation steps to produce isopentenyl pyrophosphate (IPP), a five-carbon molecule. IPP is the first hemiterpene.

Dimethylallyl Pyrophosphate (DMAPP): IPP can be isomerized to DMAPP, another five-carbon hemiterpene. These two molecules are interchangeable and form the foundation for larger isoprenoids.

53
Q

isomerisation of IPP to DMAPP

A
  1. IPP (nucleophile) picks up proton
  2. carbocation formation s base picks up proton to reform C=C
  3. forms electrophile DMAPP
54
Q

biosynthesis of terpenes

A

coupling IPP and DMAPP gives C10 unit - reaction involves addition of electrophile to a double bond = monoterpenes

this coupling process reforms the intermediate so it can keep on going

biological chemistry 2 (5 decks)

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