SECONDARY METABOLISM

of MICROORGANISM
Marlia Singgih Wibowo
School of Pharmacy ITB

Questions about
Secondary Metabolism?
What is the difference between primary
metabolism and secondary metabolism?
What is the characteristic of secondary
metabolites?
What is the function of secondary metabolites
for them and for human /mankind?
How long is the biosynthesis pathway of
secondary metabolites?
How we can manipulate the biosynthesis
pathway of secondary metabolites

Secondary metabolites categorized based

on :
Chemical Structure (e.g : cyclic nitrogen
group, beta-lactam group, etc)
Producer of metabolites (e.g :
mycotoxin, bakteriotoxin, etc.)
Activity (antibiotic, immunosuppressant,
etc.)

Biosynthetic pathway of

secondary metabolites
Simple way , with 1 product we called it
P (end product)
A

Level of P is a feedback inhibition

 Branched biosynthetic pathway, the

products P1 and P2 : together or
separately influenced the conversion of C
to D and E

P1

P2

multivalent feedback biosynthetic pathway,

where the products P1 and P2 together
influence convertion A to B, and separately
influence convertion C to D and E

P1

P2

Diversity in secondary metabolism

More than 50 varieties can be occurred
during metabolism process from one
substance produced by one
microorganism
One substance maybe consists of one or
more components with similar strctures ,
or only a few molecules difference
Example : anthraquinone and endocrocin,
or combination of vincristin, isovincristin,
rubrocristin

Me
Vincristin

Me

OH

OH

OH
O

MeO
H
OH

Me
O

O
OH

Isovincristin
Rubrocristin

Specific metabolites
In secondary metabolism , there are some
specific metabolites produced beyond the
primary metabolism
Not all secondary metabolites produced by
gathering units from primary metabolites

Secondary Metabolites with

Chlor and Bromine
Chlor (Cl) or Bromine (Br) bound
covalently with the main structure,
example : Chloramfenikol, Griseofulvin,
Chlor-tetrasiklin, pyrolnitrine, etc.
To evaluate the biosynthesis, radioactive
Chlorine can be added into growth media,
and analysed.

Substances with unusual nitrogen moiety

Several secondary metabolites contains
unusual nitrogen moieties such as nitro,
nitroso, cyano, diazo, nitrilo, isonitrilo,
hydroxamic acid, etc.
Example : Azaserin, alazopeptin,
borrelidin, toyocamisin, alanosin,
xantocillin, isonitrin A, ferrioxamine, dll.

Substances with Phosphorous

Primary metabolites which contain
Phosphorous for example ester of
phosphoric acid
Secondary metabolites which contain
fosfor, i.e. fosfonate, fosfinate,
fosfonamidate, Fosfonomisin,
plumbemisin B, fosforamidon
However, these ester can be easily
degraded so that they are difficult to be
detected .

Organometal
Secondary metabolites that contain metal
mostly in the form of Fe (iron) complex, i.e.
ferroxamine, ferricrosin, coprogen,
ferroverdin (with Fe bivalent), ferrimisin A,
etc.
Other metals are : magnesium
(magnesidin), Copper (bleomisin,
pleomisin)

Other secondary metabolites

with Boron : boromicyn,
aplasmomicyn
With amino acid : alanosin,
azaserine, diaminosuccinic acid,
Rhizobitoxin, dll

Function of secondary
metabolites
Derailed Primary Metabolism
Biochemical Appendices
Waste products, shaving from an
imperfectly functioning intermediate
metabolism
Product of detoxification mechanisms
Results of an inhibited growth
A Playing field of biochemical evolution

Biological System of microorganism has

5 important level in their development

Intermediate Metabolism
Regulation of intermediate metabolism
Transport of substrates and metabolites
Differentiation
Morphogenesis

In these stages usually secondary metabolites are formed/

produced

Classification of secondary metabolites

based on its precursor and structural
components
Nukleic acid,
polysaccaride,
glicoside

Sugars
Glikolisis

Siklus P-P

Fosfoenolpiruvat

Derivates of sugar :
glikosida,
oligosakarida,
aminoglikosida

Siccimi
c acid
pathway

aa aromatic
Protein

Unusual aa :
oligopeptida,
alkaloid

aa alifatik
Piruvat
Asetil CoA

Malonil CoA
Fatty acid

Siklus TCA

Asetoasetil CoA

Poliketida
Isoprenoid

Skualen

Secondary metabolites pathway in

fungi
Monosakarida
Aa aromatik

Energi

Metabolit sekunder

Senyawa 3 C

Gula alkohol,
disakarida,
polisakarida
cadangan
Metabolit sekunder

Metabolit sekunder
Malonil CoA
Asam
lemak

Piruvat
Asetil CoA
Siklus TCA

Metaboilit
sekunder
Energi

Mevalonat

Asam organik,
asam amino

Karotenoid,
sterol, met.2nd

POLYKETIDE
Poly of -keto acid
Subunit polyketide can be :
-CH2COacetate
-CHMeCO- propionate
-CHEtCO- butirate
If reduction process occurred in
polymerization of acetate, fatty acid will be
formed

Acetate polymerization

XS-CO-R

&

CH2-CO2-COSX

XSH + R-CO-CH2-COSX + CO2

Variation of polyketide that might be

formed
Variation 1 : form a chain of 4 units, max. 19
unit
Variation 2 : reduction of chain to form fatty acid,
then cyclication
Variation 3 : dehydration and aromatic formation
Variation 4 : addition of other units, e.g.
propionate or butirate
Variation 5 : cyclic, lacton formation

 Variation 6 : addition of Oxygen moiety

Variation 7 : addition of C-methyl and Omethyl
Variation 8 : modification of chain, e.g.
decarboxyilation at carboxyl end
Variation 9 : addition of atom Chlor or
Bromine
Variation 10 : Combination with other
polyketide moieties
Variation 11 : dimerisation

AMINO ACID as main structure

secondary metabolites contained
polyketide usually coloured, while
contained amino acid usually colorless
Some metabolites posses antibiotic
properties
Category :
unusual amino acid
Transformation of amino acid
Synthesis of amino acid
Synthesis at non-ribosome site
Bound with other polypeptide

Biosynthesis of penicilin and

cephalosporin
L--aminoadipic acid

L-cysteine

L-valine

-(L--aminoadipyl)-L-cystein

-(L--aminoadipyl)-L-cystein-D-valine

Siklisasi 2 tahap

3 precursor amino
acid:
L-valine, L-cystein,
L--aminoadipat

Isopenicilin N
C.Acremoneum, Streptomyces sp.
Penicilin N
Deacetoxycephalosporin C
Deacetylcephalosporin C

Cephalosporin C

Penicillium chrysogenum
Penicilin G

Regulation of penicillin by L-lysine in

Penicillium chrysogenum
-ketoglutarat + asetil CoA
Homositrat
Feedback
inhibition

-ketoadipat
-aminoadipat

Adenil AA-semialdehid

L-AA-cys-val

Saccharopine

Isopenisilin N
Prekursor

L-lysine

Penisilin G