FATTY ACID METABOLISMKETOGENESIS

Dr. Aga Syed SameerCSIR Lecturer

Department of Biochemistry,

Medical College,

Sher-I-Kashmir Institute of Medical Sciences,

Bemina, Srinagar, Kashmir, 190018. India.

Most of the acetyl-CoA produced by the oxidation

of fatty acids in liver mitochondria undergoes

further oxidation in the TCA cycle.

Some of the acetyl-CoA is converted to three

important metabolites: acetone, acetoacetate, and

β-hydroxybutyrate.

The process is known as ketogenesis, and these

three metabolites are traditionally known as

ketone bodies

These three metabolites are synthesized primarily

in the liver but are important sources of fuel and

energy for many peripheral tissues, including

brain, heart, and skeletal muscle

Ketone Bodies

The Ketone Bodies are important sources of

energy because:

Soluble in aqueous solution, hence need no carrier

system for transport

Produced in liver when Acetyl CoA present exceeds the

oxidative capacity

Used in proportion to their concentration in blood by

extra hepatic tissues

Ketone Bodies

Ketone Bodies -

Generation

The reaction catalysed by

Transferase (Thiophorase) is

reversible one but the product

acetoacetyl CoA is actively

removed as soon as it is produced

in peripheral tissues

Liver Does not have Thiophorase

hence it itself cannot use the ketone

bodies

Ketone Bodies - Use

Ketonemia: Levels of ketone bodies in the blood

rise above the normal levels

Ketonuria: Ketone bodies are excreted in the urine

of an individual

Both conditions are seen in Type I DM

Due to Excessive FA degradation leading to increased

production of Acetyl CoA

Depletes NAD pool and Increases the NADH pool

Ketonemia/uria

In severe ketosis

Urinary excretion of ketone bodies may be as high as

5000mg/24h

Blood Concentration of ketone bodies may be as high as

90mg/dL (Vs 3mg/dL)

Diabetic ketoacidosis is characterised by fruity

odour of the breath (Acetone)

An elevation of ketone body concentration in the

blood leads to acidemia

This is due to the carboxylic group of ketones which

has pKa of about 4

Ketoacidosis

The most prevalent steroid in animal cells is

cholesterol

Plants do not contain cholesterol, but they do

contain other steroids very similar to cholesterol

in structure

Cholesterol serves as a crucial component of cell

membranes and as a precursor to bile acids (e.g.,

cholate, glycocholate, taurocholate) and steroid

hormones (e.g., testosterone, estradiol,

progesterone)

Vitamin D3 is derived from 7-dehydrocholesterol,

the immediate precursor of cholesterol

Cholesterol

It is very Hydrophopic

Compound

Consists of four fused

Hydrocarbon rings (A, B,

C and D – Steriod

Nucleus)

In addition, it has 8

carbon, branched

hydrocarbon attached to

C17 of the D-ring

Ring A has OH- group at

C-3

Ring B has double bond

between C-5 and C-6

Cholesterol

Liver is the primary site of cholesterol

biosynthesis, in addition to Intestine, adrenal

Cortex and Reproductive Tissues

All Carbon atoms in cholesterol are provided by

acetate, and reducing equivalents are furnished

by NADPH

The pathway is driven by Hydrolysis of High

energy Thioester Bond of Acetyl CoA and ATPs

The enzymes involved are present in both Cytosol

and the membrane of ER

Synthesis

The third step in the pathway

is the rate-limiting step in

cholesterol biosynthesis

HMG-CoA undergoes two

NADPH-dependent reductions

to produce 3R-Mevalonate

The reaction is catalyzed by HMG-

CoA reductase, a 97-kD glycoprotein

that traverses the endoplasmic

reticulum membrane with its active

site facing the cytosol

As the rate-limiting step, HMG-CoA

reductase is the principal site of

regulation in cholesterol synthesis

Synthesis to Mavolonate

Three different regulatory mechanisms are

involved:

1. Phosphorylation by cAMP-dependent protein

kinases inactivates the reductase. This

inactivation can be reversed by two specific

phosphatases

2. Degradation of HMG-CoA reductase. This

enzyme has a half-life of only three hours, and the

half-life itself depends on cholesterol levels: high

[cholesterol] means a short half-life for HMG-CoA

reductase.

3. Gene expression—cholesterol levels control the

amount of mRNA. If [cholesterol] is high, levels of

mRNA coding for the reductase are reduced. If

[cholesterol] is low, more mRNA is made.

Regulation

Questions?

AssignmentRegulation of HMG CoA Reductase?