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BIOC2120 Lectures 2010: Dr. J.A. Illingworth

Integration & Compartmentation of Metabolism

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Table of contents


citrate isocitrate oxoglutarate succinyl-CoA succinyl-CoA succinate succinate fumarate fumarate malate oxaloacetate citrate synthase aconitase isocitrate dehydrogenase oxoglutarate dehydrogenase succinate thiokinase succinate dehydrogenase fumarase malate dehydrogenase acetyl-CoA pyruvate pyruvate dehydrogenase pyruvate carboxylase whitespace

An urban myth:

This is designed to refresh your knowledge of "classical" hormonal regulation of metabolism [see chapters 18 in Tortora & Derrickson, chapters 18 & 19 in Kumar & Clark]. In recent years numerous additional hormones and cytokines have been discovered, and we will mention some of these in the next four lectures.

A young woman lies asleep dreaming of a holiday abroad. Her bed is warm and comfortable but she stirs slightly in the small hours as the sky begins to lighten and her stomach reminds her that it is almost time for breakfast.

Suddenly she awakes and looks at the clock. "Oh ****!" she says, and leaps from the bed, frantically pulling on her clothes. Skipping breakfast and her morning shower she races from the house and sprints for the bus stop at the far end of her street. She makes the bus with seconds to spare and collapses on a seat to regain her breath.

By the time she gets to work about 30 minutes later she has almost recovered her composure. She puts her head round the bosses door: "I missed breakfast, but have I time to do my hair before the interview?"

"It's okay" says the bosses secretary "he's rung in sick. You can get your breakfast in the staff canteen."

By this stage she is really hungry, and orders poached eggs on toast with sausages and baked beans, washed down with a big mug of coffee, and some more toast and marmalade. As she settles down to read the newspaper, she realises that she needs to visit the loo...

Worse things happen at sea! Human beings regularly survive war zones and shipwrecks, major injuries and infectious disease. Our ability to live a free and independent life depends on the precision and reliability of our metabolic control systems. Over the next 20 years this woman will travel widely, raise a family, and cope with all of life's vicissitudes while relying on strategies that started two thousand million years ago.

Some self-directed learning:

Which hormone was released in waves from her pituitary gland as she dreamed of her holiday abroad?
[It acted mainly on her liver, which released a second polypeptide hormone with widespread effects.]

Which hormone was released in larger quantities as dawn was breaking?
Where did it come from and what did it do?

Which hormone was released as she sprinted for the bus?
Where did it come from and what did it do?

How did she control her blood sugar as she recovered on the bus and prepared for her interview?
Which hormones were active?

Which systems were activated as she watched the sausages sizzling in the pan?
How did they "know" what to expect?

Which hormones were being released as she put the lid back on the marmalade?
What did they do?

How did she know how much to eat, and why did she need the loo?

What do you need to know first?

Learning Biochemistry is like learning a foreign language: you must know the vocabulary as well as the grammar. Students are often overwhelmed by the flood of new information, because they have not taken the time to learn the basic material from the first year course. Without this fundamental knowledge, many of the advanced concepts will go straight over your head. Here is a list of some of the things you ought to know:

Amino acids: you should know all 20 amino acids that occur in proteins - structures, names and single letter abbreviations. You need them both ways round - see the name: write the structure; see the structure: write the name. Strictly speaking, you will only need seven for Illingworth's lectures (alanine, aspartate, glutamate, glutamine plus arginine, ornithine and citrulline from the urea cycle) but you will also need the aromatics for the PKU problem and you will need the whole ensemble for protein structures. You might as well learn them all now - they will come in handy later.

Nucleotides: You need instant recognition of A, T, G and C plus ribose and deoxyribose. You should also know NAD, NADP, FAD, FMN and ubiquinone in their oxidised and reduced forms.

Sugars: Glucose, fructose and galactose plus maltose, sucrose and lactose. Don't try to remember exactly which way the hydroxyl groups point, but recall that glucose is the world's most popular sugar because it is the only one where ALL the bulky groups can reach the unhindered equatorial position in the most stable "chair" configuration. Know glycogen, starch and glyceraldehyde.

Lipids: You should be able to recognise triglyceride, diacylglycerol and the most common phospholipids: lecithin, phosphatidyl inositol, phosphatidyl ethanolamine and phosphatidyl serine. Don't worry about the orientation of the hydroxyl groups on inositol.

Intermediates: You definitely need to recognise and draw all eight of the Krebs' cycle acids, plus most of the glycolytic intermediates and the fatty acid biosynthetic and degradation spirals. This isn't as daunting as it seems, given the starting and finishing points there is only one sensible way to do the chemistry in between. Many of the reaction sequences recur in different pathways. Notice the structural relationships between the simple common amino acids [A, C, D, E, G, N, P, Q, S] and the corresponding metabolic intermediates. By the end of this module you will have also learned many of the steroid and porphyrin pathways.

Learning technique: You must put pen to paper - you will never learn them by staring at a book. You can do this easily in one evening, but there is a technique:

Copy all the names and structures from your textbook. Some people use cards: names on the back, structures on the front. Close the book, cover the names and study the structures. Name as many as you can from memory. Write them down. Check them. Repeat any that you didn't know, or got wrong the first time round. Do it again and again, varying the order and concentrating on the ones you didn't know until you get them all correct.

Now do it the other way round. Draw as many structures as you can from the list of names. Check them. Repeat any that you didn't know, or got wrong the first time round. Do it again and again, concentrating on the ones you didn't know until you get them all right.

The lecture handouts are skeleton notes to guide you in your work. They are not sufficient by themselves, and we expect you to make additions to them from the lectures and textbooks, and from this website.

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Recommended Textbooks

Many general Biochemistry texts cover the core information required for the course. There are multiple copies in the University Libraries. e.g.

For basic information on hormones try: Tortora & Derrickson (2008) Principles of Anatomy & Physiology 12th edn. or Kumar & Clark (2009) Clinical Medicine 7th edn.

Some useful books about the metabolic syndrome and obesity:

Bioenergetics is taught and examined in the BIOC2300 module, but you need some of this information to understand the BIOC2120 course. If you are not also taking BIOC2300, please contact Dr Illingworth for additional help.

Nicholls & Ferguson (2002) Bioenergetics 3 (Academic Press) contains useful information for lecture 2 on metabolic compartmentation. The bioenergetics chapters are also uesful in Alberts et al (2008) Molecular Biology of the Cell 5th edn. Garland Science. [chapter 14] and Lodish et al (2007) Molecular Cell Biology 6th edn. W H Freeman. [chapter 16]. Some background material on bioenergetics can be found at http://www.bmb.leeds.ac.uk/illingworth/oxphos/index.htm and on metabolism in general at http://www.bmb.leeds.ac.uk/illingworth/metabol/index.htm (part of this website).

The metabolic syndrome:

There is a recognised association between abdominal obesity, type 2 (insulin resistant) diabetes, dislipidaemia (abnormal blood lipids), hypertension (high blood pressure) and cardiovascular disease (mainly heart attacks and strokes). This group of related conditions is often referred to as the metabolic syndrome because they seem to share an endocrine or metabolic cause. It is increasingly clear that the immune system plays a major part in these pathological processes. These diseases are all associated with chronic low-grade inflammation affecting the blood vessel walls.

Make sure that you fully understand the difference between "Juvenile Onset" Type 1 diabetes, which is caused by autoimmune destruction of the pancreatic β-cells, typically in children, and "Maturity Onset" type 2 diabetes which is caused by insulin resistance in the target tissues, and typically occurs in obese middle-aged adults. Type 1 diabetics have no circulating insulin and always require insulin injections, but type 2 diabetics may have high circulating insulin and are initially treated with dietary restriction, exercise and oral hypoglycaemic drugs.

measurementhealthy rangemetabolic syndromecommentspathology

body mass index

18 - 25 kg/m2

> 30 kg/m2

includes muscle mass

abdominal
obesity

waste : hip ratio (males)

0.85

> 0.9

measures abdominal obesity

waste : hip ratio (females)

0.7

> 0.85

measures abdominal obesity

fasting blood glucose

4.5 - 5.5 mM

> 7 mM

ideally 5 mM

type 2
diabetes

fasting blood insulin

5 - 10 µUnits/mL

20 - 40 µUnits/mL

1 µUnit/mL = 6.945 pM

fasting triglycerides

0.5 - 1.5 mM

> 1.7 mM

much higher after a big meal

dislipid
-aemia

total cholesterol

3.5 - 5.5 mM

> 6 mM

ideally 5 mM

LDL-cholesterol

2.0 - 3.0 mM

> 3.3 mM

"bad" cholesterol

HDL-cholesterol

1.1 - 2 mM

< 0.9 mM

"good" cholesterol

blood pressure (mm Hg)

120 / 80

> 140 / 90

systolic / diastolic

hypertension

C-reactive protein

< 3 mg/L

> 3 mg/L

measures inflammation

inflamation

These are "broad brush" indications. Detailed figures vary with age, and often differ between men and women, and for different races.

Cardiovascular diseases are the major cause of mortality and morbidity (death and ill-health) throughout the developed world. The incidence varies considerably with race, age and sex, but is typically around 40% of all deaths. [This is higher than all types of cancer added together.] Cardiovascular disease is responsible for a disproportionate number of preventable deaths in people under 75 years of age, and causes significant reductions in quality of life among survivors: severe physical disability, blindness, amputations and kidney disease. People with a South-Asian ancestry who adopt a "western" lifestyle are particularly at risk from the metabolic syndrome, but all races are susceptible to these conditions. Cardiovascular disease is strongly associated with smoking and low socio-economic status. Glasgow used to have the highest incidence of heart disease in the UK. This rate is falling, possibly in response to public health education campaigns.

The data below is taken from from Willet et al. (1999) Guidelines for Healthy Weight New England Journal of Medicine 341, 427 - 433.

Although we do not fully understand the pathological process involved in the metabolic syndrome, these are believed to involve pro-inflammatory cytokines such as TNF-α primarily secreted by the immune system, but also secreted by bloated adipocytes, which are fat storing cells derived from the fibroblast lineage. It is therefore important to study the complex relationships between diet, metabolic processes, and the numerous hormones secreted by adipocytes, lymphocytes and endocrine cells that help to regulate metabolic activity in humans.

Treatment

The basic message is to lose weight, and if patients succeed in doing this, all aspects of their condition will spontaneously improve. Unfortunately this is easier said than done. It is VERY difficult to voluntarily lose 10% of your body weight, and 20% is almost impossible. This is because there are powerful negative feedback systems working in the opposite direction, and we will study these in lecture 4. Even if a patient manages to lose weight by lifestyle changes, these changes must be permanent or they will quickly put it all back on again.

Effective weight loss means eating less and exercising more. The exercise is essential - it is extraordinarily difficult to lose weight be dieting alone. There is an excellent paper by Ness et al (2007) Objectively measured physical activity and fat mass in a large cohort of children. PLOS Medicine 4, 476-484 which shows the effects of exercise on child obesity in Bristol. In addiiton to "burning off" surplus calories, the exercise has valuable anti-inflammatory effects. The metabolic syndrome is an inflammatory state, and simple anti-inflammatory drugs like aspirin have an important role in the treatment of cardiovascular disease. The statins used to inhibit cholesterol biosynthesis also have significant anti-inflammatory effects.

Many drug companies are actively seeking appetite-suppressing drugs. The potential market is huge and projected profits are enormous. Unfortunately it is far from easy to design an effective drug, and many of those developed so far have proved to have serious side effects. Eating is a hugely pleasurable activity, and attempts to interfere with it make patients miserable, bad-tempered and homicidal. This shows up rather clearly in the stats.

We will keep returning to this topic in the subsequent lectures.

Some good websites on the metabolic syndrome:

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Don't forget to try the self-assesment tests!

introduction

metabolic map

lecture 1

lecture 2

lecture 3

lecture 4

self-assessment



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