Part 5: “Isoprenoids” terpenes & steroids - UMass D 5: “Isoprenoids” terpenes & steroids . Terpenes: Lipids composed of 5- C building blocks joined together to form chains

Part 5: “Isoprenoids” terpenes & steroids Terpenes: Lipids composed of 5-C building blocks joined together to form chains & rings Basic 5C unit = “isoprenes”, joined head-to-tail to make skeleton “Terpenoids” have undergone additional functionalization, usually oxygen-based groups Terpenes & terpenoid skeletons usually contain some multiple of 5 carbons; groups are named accordingly. Larger terpenoids like steroids may lose a few C during later biosynthetic steps The pattern of isoprenes can still be seen intact in some of the common terpenes; others have undergone rearrangements to alter the skeleton somewhat.

Limonene

Terpene biosynthesis All terpenes are built using the isoprene unit, derived from isopentenyl pyrophosphate (IPP). IPP is formed through a series of Claisen condensations and aldol additions (Ch. 23).

For assembly to occur, IPP undergoes an enzyme- catalyzed isomerization to form DMAPP

How the units join: Because PP is a good leaving group, DMAPP forms the allylic carbocation, which reacts with another IPP, forming geranyl PP (10 C). Further 5C units add in the same way.

Two 15 carbon FPPs join tail to tail to make squalene (precursor to steroids)

Many compounds from the same skeleton: Monoterpene essential oils Ring-closure reactions proceed by a mechanism similar to the addition of IPP to DMAPP • (E)-geranyl PP first converts to (Z)-geranyl PP, bringing carbons closer for ring closure • Carbocation intermediates provide pathway to a variety of compounds: • Deprotonation of these carbocations leads to unsaturation • Hydration of any carbocations puts OH groups on the skeleton • Oxidations of any of these OH groups results in aldehydes, ketones and carboxylic acids

Some larger medicinal terpenes:

from chamomile, has wound-healing and antibacterial properties

artemesinin from Artemesia annua used as anti-malarial

From squalene to steroids Squalene (a triterpene, 30C) is the precursor of all steroids and plant sterols The biosynthetic route involves: • Epoxidation at one end of the chain • A series of cyclizations leading to formation of characteristic 4-ring skeleton • Rearrangement of resulting protosterol cation by hydride or methyl shifts leads to lanosterol, a precursor of cholesterol and plant sterols

Cholesterol: main functions and properties • Cell membrane structure & fluidity • Precursor of steroid hormones and bile acids • Carried by lipoproteins in esterified form • Molecule is flat due to the trans-fused configuration of the B, C & D rings • 8 chiral carbons = 256 possible stereoisomers (only one occurs in nature!)

Diet, medicine and cholesterol levels • Most cholesterol in the body is not directly from food sources but biosynthesized in response to body’s needs • Excess dietary cholesterol can inhibit uptake by cells • Dietary fats can affect cholesterol transport & metabolism • High HDL levels reduce cholesterol level in bloodstream • Many cholesterol-lowering drugs (statins) work by interfering with cholesterol biosynthesis • Statin structure mimics that of HMG Co-A, a key enzyme in IPP biosynthesis

How folding and cyclizations lead to sterols & triterpenes

Folding pattern leading to protosteryl cation, precursor of cycloartenol & lanosterol

A and B rings may be fused in trans or cis conformation; other rings are trans

Steroids: C18-27 skeleton Derived from cholesterol Usually 4 rings plus a side chain Many of the carbons get oxidized to alcohol or ketone groups Some unsaturation, position varies Estrogens have an aromatic ring

“Phytoestrogens” mimic estrogen’s shape