KLASIFIKASI SENYAWA BAHAN ALAM

Dasar : Bentuk struktur, ada kaitannya dengan asal usul

biogenesis

Biogenesis : suatu propuse/ usulan terjadinya sintesis

senyawa di alam berdasarkan teori-teori kimia organik

Biosintesis : sintesis senyawa alam yang prosesnya telah

diketahui dengan pasti, enzim yang terlibat atau reaksi
dalam tumbuhan yang diikuti dengan reaksi bertanda,
datanya didukung oleh penelitian laboratorium
 Jalur utama biosintesis senyawa bahan alam

Fenil propanoid;
Asam shikimat Tirosin
alkaloid

Flavonoid;
polifenol;
stilbenoid
Karbohidrat
Gabungan jalur shikimat-
asam asetat

Asam Terpenoid;
Asam asetat mevalonat steroid
Ciri-ciri Jalur asetat-mevalonat :
1. sangat beragam, tingkat oksidasi tinggi
2. terdapat pada tumbuhan dengan tingkat evolusi relatif muda
3. Tumbuhan banyak dengan bentuk semak/ perdu, misalnya
famili compositae
4. struktur aromatik, ada oksigen berselang-seling

Ciri-ciri jalur Shikimat

1. Struktur biasanya C6 –C3, ada aromatik
2. dijumpai cincin heterosiklik (alkaloid)
3. Tumbuhan dengan tingkat evolusi relatif tua, misal famili
Papaveraceae, Dipterocarpaceae
4. Tumbuhan pohon tinggi, misalnya hutan tropika
(mengandung polifenol)
TERPENOID
 Terpenoid
• Merupakan metabolit sekunder yang tersebar sangat luas
di alam, strukturnya paling beragam dan fungsinya mulai
dari volatile sex pheromones sampai ke karet alam.
• Nama “terpenoid” disebut juga “terpen” diambil
berdasarkan senyawa yang pertama kali berhasil
diisolasi yaitu “terpentin”.
• Dibangun oleh kerangka dasar isoprena (5 karbon)
• Senyawa-senyawa terpenoid dibentuk dari pengulangan
(polimerisasi) ikatan antar unit-unit isoprena “head to
tail”, siklisasi dsb.

isoprena
• Ikatan antar unit isopren dapat dibentuk secara :
– A. linear / ikatan kepala –ekor

kepala – kepala

kepala – bagian tengah

– B. siklik /siklisasi pengulangan unit

• Unit-unit isopren ganda dalam suatu terpen berfungsi untuk
klasifikasi.
 Klasifikasi Terpenoid
• Monoterpen (2 isopren) C10H16
• Sesquiterpen (3 isopren) C15H24
• Diterpen (4 isopren) C20H32
• Sesterpen (5 isopren) C25H32
• Triterpen (6 isopren) C30H48
• Tetraterpen C40H64
• Politerpen (C5H8)n, >8 unit isopren
 Monoterpen
• Terdiri dari 2 unit isopren
• Merupakan komponen minyak esensial (essential oil) pada
herba dan rempah-rempah dan sebagai attractant
• Besarnya sekitar 5% berat kering tumbuhan
• Diisolasi dengan distilasi/penyulingan dan ekstraksi 
pada industri parfum
 Sesquiterpen
• Terdiri dari 3 unti isopren
• Merupakan komponen minyak esensial
• Banyak diantara anggota sesquiterpen berfungsi
sebagai fitoaleksin, senyawa antibiotik yang
diproduksi tanaman sebagai respon adanya
serangan mikroba, dan sebagai antifeedant (agar
tidka dimakan/tidak disukai predator herbivora).
• Salah satu contoh : hormon asam absisat, asam
turmerone pada Curcuma longa
 Diterpen
• Terdiri dari 4 unit isopren
• Fungsi sangat bervariasi
• paling penting isoprenoid asiklik fitol(sisi hidrofobik
klorofil), terdapat pada berbagai gliserida eter lipid bakterial
sebagai dihidrofitol (fitanol)
– Hormon giberelin
– Resin (conifer dan legum)
– Fitoaleksin
– Taxol (antikanker)
– Forskolin (obat glaucoma)
 Triterpen
Tetraterpen
• Terdiri dari 6 unit isopren Terdiri dari 8 unit isopren
• Contoh-contoh : Fungsi : pigmen
– brassinosteroid (hormon) fotosintesis
– Fitosterol
Contoh : karotenoid
– Fitoaleksin tertentu
– Komponen lapisan lilin
– Asam oleanolik (pada anggur)
 Biosintesis terpenoid secara umum
Biosintesis semua senyawa terpenoid dapat dijelaskan
menjadi 4 tahap,yaitu :
1. Sintesis prekursor dasar IPP (isopentenil pirofosfat).
2. Pengulangan/penambahan IPP ke bentuk homolog
dari prenil difosfat (menjadi terpenoid yang berlainan
kelompok).
3. Modifikasi enzimatik pertama, perluasan prenil
difosfat oleh enzim terpenoid sintase spesifik
membentuk rangka terpenoid.
4. Modifikasi enzimatik kedua, membentuk struktur
kimia khas masing-masing jenis senyawa (biasanya
lewat reaksi reduksi-oksidasi)
 Tempat biosintesis dan akumulasi senyawa
terpenoid
• Terpenoid disintesis oleh tumbuhan, hewan, dan
mikroorganisme
• Melibatkan enzim-enzim yang serupa, tetapi proses
biosintesisnya berbeda
• Tumbuhan memproduksi senyawa terpenoid
dengan variasi yang lebih luas dibandingkan
dengan hewan atau mikroorganisme
• Umumnya diperlukan struktur khusus untuk
menyimpan senyawa terpenoid
 Tempat biosintesis dan akumulasi senyawa
terpenoid…
• Contoh :
– Trikoma/kelenjar trikoma
– Kelenjar pada epidermis petala (kaitannya dengan
penyerbukan)
– Saluran resin (konifer)
– Epidermis dan sel laticifer  lateks dan lilin
• Sesquiterpen, triterpen, dan politerpen
diproduksi dalam sitosol dan retikulum
endoplasma (RE)
 Tempat biosintesis dan akumulasi senyawa
terpenoid…
• Diterpen dan tetraterpen diproduksi/disintesis
di plastida
• Jalur biosintesis terpen pada masing-masing
organel tersebut berbeda.
– Pada sitosol dan RE  prekursor IPP dibentuk
lewat jalur asam mevalonat
– Pada plastida  prekursor IPP dibentuk lewat jalur
asam piruvat
Senyawa yg sebenarnya terlibat adalah isopentenil pirofosfat (IPP)
yg terbentuk dari asetat melalui asam mevalonat.IPP terdapat di
dlm sel hidup dan berkesetimbangan dg isomernya yaitu dimetilalil
pirofosfat (DMAP).

1 molekul DMAP disambung dg 1 IPP membentuk

Geranil Pirofosfat (GPP) yg merupakan syw antara yag
merupakan kunci pd pembentukan monoterpena (C10).

GPP disambung dg IPP terbentuk Farnesil pirofosfat

(FPP) yaitu senyawa antara pada sintesis
seskuiterpena (C15).

FPP disambung dg IPP terbentuk Geranil-geranil

Pirofosfat (GGPP)
The Mevalonate Pathway to
Isopentenyl Diphosphate
1. Begins with conversion of
acetate to acetyl CoA Claisen
condensation yields
acetoacetyl CoA
2. Second Claisen condensation
reaction with third molecule of
acetyl CoA yields six-carbon
compound 3-hydroxy-3-
methylglutaryl CoA
3. 3-Hydroxy-3-methylglutaryl
CoA is reduced to mevalonate
4. Phosphorylation with loss of
CO2 and phosphate ion
completes synthesis
 Terpenoids
STEP 1 OF FIGURE 23.12: CLAISEN CONDENSATION
First step in mevalonate biosynthesis is a Claisen condensation to yield
acetoacetyl CoA
• Catalyzed by acetoacetyl-CoA acetyltransferase
• Acetyl CoA is first bound to enzyme by nucleophilic acyl substitution
reaction with cysteine –SH group
• Formation of enolate ion from second molecule of acetyl CoA
followed by Claisen condensation yields product
 Terpenoids
STEP 2 OF FIGURE 23.12: ALDOL CONDENSATION
Acetoacetyl CoA undergoes an aldol-like addition of an acetyl CoA enolate
ion
• Reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA synthase
• Occurs by initial binding of substrate to cysteine –SH group followed by
enolate addition and hydrolysis
 Terpenoids
STEP 3 OF FIGURE 23.12: REDUCTION
Reduction of HMG-CoA to give (R)-mevalonate is catalyzed by 3-hydroxy-
3-methylglutaryl-CoA reductase
• Requires 2 equivalents of NADPH
• Reaction occurs in two steps and proceeds through an aldehyde
intermediate
– Nucleophilic acyl substitution involving hydride transfer from
NADPH to thioester carbonyl group of HMG-CoA
– CoA is expelled and aldehyde undergoes second hydride addition
to give mevalonate
 Terpenoids
STEP 4 OF FIGURE 23.12: PHOSPHORYLATION AND DECARBOXYLATION
Three additional reactions convert mevalonate to isopentenyl
diphosphate
• Two phosphorylations on terminal phosphorus of ATP catalyzed by
mevalonate kinase
• Phosphorylation of tertiary hydroxyl group followed by
decarboxylation and loss of phosphate ion
 Terpenoids
– Final decarboxylation is catalyzed by mevalonate-5-
diphosphate decarboxylase
• Substrate is phosphorylated on tertiary –OH group by ATP
• Tertiary phosphate spontaneously dissociates (SN1)
• Tertiary carbocation acts as electron acceptor to facilitate
decarboxylation
• Isopentenyl
Terpenoids
diphosphate (IPP)
and dimethylallyl
diphosphate (DMAPP)
combine to give C10
geranyl diphosphate
(GPP)
• Combination of GPP
with another IPP
gives C15 farnesyl
diphosphate (FPP)
• Reductive
dimerization of FPP
yields squalene
 Terpenoids
Mechanism of coupling DMAPP with IPP to give GPP catalyzed by
farnesyl diphosphate synthase
• Process requires Mg2+ ion
• Key step is a nucleophilic
substitution reaction
SN1 (DMAPP)
IPP double bond
acts as nucleophile
displacing Ppi
 Terpenoids
• Further conversion of geranyl diphosphate into
monoterpenoids involves carbocation intermediates
– Catalyzed by terpene cyclases
– Geranyl diphosphate isomerizes to allylic isomer linalyl
diphosphate (LPP)
• Catalyzed by monoterpene cyclases
• Isomerization converts C2-C3 double bond of GPP into a
single bond
– Makes cyclization possible
– Allows E/Z isomerization of double bond
– Dissociation and cyclization by electrophilic addition of
cationic carbon to terminal double bond gives cyclic cation
S N1
 Terpenoids
Mechanism of the formation of the monoterpene limonene
from geranyl diphosphate
 Worked Example 23.1
Proposing a Terpenoid Biosynthesis Pathway

Propose a mechanistic pathway for the biosynthesis

of a-terpineol from geranyl diphosphate
 Worked Example 23.1
Proposing a Terpenoid Biosynthesis Pathway
Strategy
• a-Terpineol, a monoterpenoid, is derived
biologically from geranyl diphosphate through its
isomer linalyl diphosphate (Fig. 23.15)
• Draw the precursor in a conformation that
approximates the structure of the target
molecule
• Carry out a cationic cyclization using the
appropriate double bond
• Since the target is an alcohol, the carbocation
resulting from cyclization evidently reacts with
water
 Worked Example 23.1
Proposing a Terpenoid Biosynthesis Pathway

Solution
 Steroids
Steroids are lipids derived from the triterpenoid lanosterol
• Structures are based on a tetracyclic ring system
– Four rings designated A, B, C, and D
– Numbering begins in A ring
– A, B, and C rings adopt chair conformations but do not undergo
cyclohexane ring-flips
 Steroids
Two cyclohexane rings can be joined in either a cis or trans manner
• Cis fusion gives cis-decalin
– Both groups at
ring-junction
positions (angular
are on same side
of two rings
• Trans fusion
gives trans-decalin

– Groups at ring
junction are on opposite sides
 Steroids
Steroids can have either a cis or trans fusion of the A and B rings
• Other ring fusions (B-C and C-D) are usually trans

A-B trans steroid has C19 angular methyl group up, denoted b,
and the C5 hydrogen atom down (, denoted a, on opposite
sides of the molecule

A-B cis steroid has both C19 angular methyl group and C5
hydrogen atom on the same side (b) of the molecule
 Steroids
Steroid conformations
 Steroids
Substituent groups on steroid ring system can be either axial
or equatorial
• Equatorial substitution is generally more stable for steric
reasons
– Cholesterol (has C3 hydroxyl group equatorial
 Steroids
Steroid Hormones
Steroids function as hormones in humans
• Hormones are chemical messengers that are secreted by
endocrine glands and carried through the bloodstream to
target tissues
• Two main classes of hormones
– Sex hormones
• Control maturation tissue growth, and reproduction
– Adrenocortical hormones
• Regulate metabolic processes
 Steroids
SEX HORMONES
Testosterone and androsterone are the two most important male sex
hormones or androgens
• Responsible for development of male secondary sex characteristics
during puberty
• Synthesized in the testes from cholesterol
Androstenedione is misused by athletes for muscle growth
 Steroids
Estrone and estradiol are the two most important female sex hormones,
or estrogens
• Estrogens are synthesized in the ovaries from testosterone
• Responsible for development of female secondary sex characteristics
and for regulation of menstrual cycle
Progestin is another kind of sex hormone responsible for preparing the
uterus for implantation of a fertilized ovum during pregnancy
• Progesterone is the most important progestin
 Steroids
ADRENOCORTICAL HORMONES
Adrenocortical steroids are secreted by the adrenal glands
• Mineralocorticoids Aldosterone
– Control tissue swelling by regulating cellular salt balance between Na+
and K+
Glucocorticoids Hydrocortisone
– Involved in regulation of glucose metabolism and in the control of
inflammation
 Steroids
SYNTHETIC STEROIDS
Steroids synthesized in pharmaceutical laboratories for new applications and
treatments
• Oral contraceptives
– Most birth-control pills are a mixture of two compounds
1. Synthetic estrogen, such as ethynylestradiol
2. Synthetic progestin, such as norethindrone
• Anabolic steroids
– Methandrostenolone (Dianabol) induces tissue building
in a manner similar to natural testosterone
 23.10 Biosynthesis of Steroids
Steroids are heavily modified triterpenoids that are biosynthesized
from farnesyl diphosphate (C15)
• Reductive dimerization yields squalene which is converted into
lanosterol
 Biosynthesis of Steroids
Lanosterol biosynthesis
• Begins with selective
conversion of squalene
to its epoxide, (3S)-2,3-
oxidosqualene
• Catalyzed by squalene
epoxidase
• The flavin alcohol is
dehyrated to give FAD,
which is reduced back to
FADH2 by NADPH
 Biosynthesis of Steroids
• Second part of lanosterol biosynthesis catalyzed by
oxidosqualene:lanosterol cyclase
– Enzyme folds squalene into alignment for a cascade of
successive intramolecular electrophilic additions and
hydride or methyl migrations
– Process involves discrete carbocation intermediates
stabilized by electrostatic interactions with electron-rich
aromatic amino acids in the enzyme
Biosynthesis
of Steroids

Mechanism of the
conversion of
2,3-oxidosqualene
to lanosterol
Biosynthesis of
Steroids
Mechanism of the
conversion of
2,3-oxidosqualene
to lanisterol
(continued)
 Biosynthesis of Steroids
STEPS 1-2 OF FIGURE 23.19: EPOXIDE OPENING AND INITIAL
CYCLIZATIONS
Cyclization begins in step 1 with protonation of the epoxide ring
by an aspartic acid residue in the enzyme
• Nucleophilic opening of protonated epoxide by C5,C10 double
bond then yields tertiary carbocation at C10
• Addition of C10 to C8,C9 double bond in step 2 gives bicyclic
tertiary cation at C8
Biosynthesis of
Steroids
STEP 3 OF FIGURE 23.19: THIRD CYCLIZATION
Third cationic cyclization occurs with non-Markovnikov
regiochemistry and gives secondary carbocation
at C13 rather than tertiary
carbocation at C14
• Tertiary carbocation may
be formed initially
• Rearrangement to
secondary
carbocation
probably stabilized
by electron-rich
aromatic ring in
enzyme pocket
Biosynthesis of
Steroids
STEP 4 OF FIGURE 23.19: FINAL CYCLIZATION
The last cyclization occurs in step 4 by addition of the cationic center at
C13 to the 17,20 double bond giving the protosteryl cation
• Side-chain alkyl at C17 has b (up) stereochemistry
Biosynthesis of
Steroids
STEPS 5-9 OF FIGURE 23.19: CARBOCATION REARRANGEMENTS
Carbocation rearrangements on tetracyclic carbon skeleton of
lanosterol
1. Hydride migration from C17 to C20 which establishes (R)
stereochemistry at C20
2. Hydride migration from C13 to C17 on bottom face (a)
3. Two methyl group migrations from C14 to C13 on top (b) face and
from C8 to C14 on the bottom (a) face
Histidine residue in enzyme deprotonates b proton from C9 giving
lanosterol
Biosynthesis of
Steroids
Lanosterol is further modified to yield cholesterol
• Cholesterol is the common precursor from which all other
steroids are derived