Category Archives: Biochemistry

Metabolic Disorders: Part I

Annalies Corse BMedSc, BHSc, Masters Candidate (USYD).

 

Question anyone on the concept of metabolism, and you will surely receive responses supporting that everyone knows about it. Young children learn of its existence at school; science students worldwide study the intricate metabolic reactions of living cells and the general public speaks this technical term during social banter around food and weight. However, metabolism is a facet of human health involving far more than the breakdown of food or the production of energy. Metabolism, and the biomedical understanding of metabolic disorders is one of the five pillars of health supporting the philosophy behind the MINDD Foundation. Over a series of articles, these five pillars will be presented and discussed to help you understand the importance of each for human health, including the biomedical, nutritional and lifestyle measures to improve your own health, your family’s health and safeguarding the health of generations to come.

 

Research and education into the role of Metabolic disorders in Pediatric health is fundamental to the work of the MINDD Foundation. This two part article serves to explain the importance of metabolism to our overall state of health, list the conditions associated with errors in metabolism (including the cause of such errors) and what can be done to prevent the potentially devastating consequences of errors of metabolism.

 

Definition of Metabolism

 

Metabolism occurs at the cellular and even subcellular level within tiny structures known as organelles. It is usually defined and interpreted in biochemical terms, where all reactions of the metabolic system are considered together.  In the most simplistic definition, metabolism is defined as the sum total of all chemical reactions in the body. Metabolism is comprised of:

 

  • Anabolism: chemical reactions where substances are synthesized or ‘built up’. For example: the synthesis of hormones, new tissue and antibodies, to name a few.

 

  • Catabolism: chemical reactions where substances are degraded or ‘broken down’. For example: the breakdown of food for energy production and the generation of metabolic waste products such as ketones, urea and lactate to name a few.

 

Therefore, every single chemical reaction in your body is part of your metabolism. Every useful chemical substance your body makes for you, and every waste product generated is part of your metabolism. These metabolic reactions differ depending on which organ of the body you are looking at. For example, the reactions of thyroid metabolism are completely different from reactions in skeletal muscle; every tissue and organ has a completely different role to play and their metabolic chemical reactions reflect this. Your metabolism represents far more than just weight loss and weight gain.

 

Errors in Metabolism +Causes

 

Inborn errors of metabolism are a very large group of rare and congenital disorders of metabolism, where babies are born with a genetic defect involving a specific aspect of their metabolism. These conditions are usually inherited. Most are due to single genetic mutations, where the faulty gene leads to the production of a faulty enzyme. The faulty enzyme produced is unable to catalyze its specific chemical reaction in the body (each enzyme in the human body is highly precise and usually only facilitates one specific chemical reaction). The resulting problems are incredibly varied, depending on the gene and enzyme product involved. Some conditions can be managed well, while others can be lethal errors. Depending on the actual condition inherited, symptoms can range from acute and late-onset acute, through to progressive, generalized and permanent symptoms.

 

List of Conditions

 

There are hundreds of inherited metabolic disorders, and most are exceedingly rare. As a whole, metabolic disorders usually involve a gene/enzyme product involved in:

 

  • Carbohydrate metabolism: these are usually detected in infancy and cover a vast range of conditions where specific aspects of carbohydrate metabolism are impaired. Energy production in vital organs can be severely compromised. Depending on the exact problem, these conditions are often supported by dietary interventions. Some better-known examples in this category are galactosaemia, lactose intolerance and glycogen storage diseases.
  • Amino acid metabolism: these metabolic conditions involve either the synthesis of vital amino acids, or impairment of amino acid degradation. These are so many diseases in this category, however Phenylketonuria (PKU), Homocysteinuria and Maple Syrup Urine disease are some well-known examples. If a vital amino acid is not synthesized, it is unavailable for its many roles within the body. If an amino acid is not degraded properly, it can build up, causing damage to specific tissues and organs. Dietary interventions are often used to abate the effects of these diseases.
  • Organic acid metabolism: these involve the branched chain amino acids (isoleucine, leucine and valine). If a specific amino acid cannot be broken down, its build-up can lead to academia (dangerously low blood pH) and vital organ damage. Specific dietary interventions are required, and these often commence in infancy.
  • Fatty acid metabolism: many enzymes are required to break down fatty acids for energy; a problem with any one of these enzymes is known as an inborn error of lipid (fat) metabolism. Some involve carnitine (which helps transport fatty acids to your mitochondria for energy production), while others prevent correct lipid storage. Yet another vast category.
  • Mitochondrial metabolism: these have a huge array of presentations, but ultimately involve impairment of mitochondrial function and ultimately the production of energy as a whole.
  • Porphyrin metabolism: porhyrin rings are specific chemical structures found in vital substances such as haeme (predominantly found in red blood cells) and cytochromes (found in mitochondria for energy production and also in hepatic tissue for detoxification). When not synthesized or degraded properly, they are classified as metabolic diseases known as Porphyrias. It is believed that Pyrrole Disorder may belong to this category.
  • Purine and pyrimidine metabolism: purines and pyrimidine’s are essential chemicals produced by the body and contribute to the structure of DNA, RNA and energy molecules such as ATP to name just a few. Defective enzymes governing purine and pyrimidine metabolism affect the normal sequences of human DNA, meaning harmful mutations are common in this group of metabolic diseases.
  • Peroxisomal metabolism: peroxisomes are organelles involved in breaking down very long chain fatty acids for energy.
  • Steroid metabolism: human steroid hormones include oestrogen, progesterone, testosterone, cortisol, and aldosterone. All steroid hormones are derived from cholesterol. Each condition varies, depending on the exact enzyme and hormone involved. Disorders of secondary sexual characteristics, ambiguous genitalia and adrenal insufficiency all come under this category.
  • Lysosomal storage diseases. Lysosomes are organelles, and can be described as the recycling centre of the cell. Unwanted substances can be converted into useful substances for a cell by lysosomes. Metabolic disorders involving lysosomes result in the accumulation of cellular waste, leading to cellular and organ damage.

 

Due to the overwhelming number of metabolic disorders, diagnosis in a clinical setting can be difficult. The range of signs and symptoms that could possibly present is enormous. In general, infants and children who present with the following signs/symptoms may be investigated for a congenital metabolic disease, depending on their entire clinical picture and medical case history:

 

  • Failure to thrive
  • Growth failure
  • Developmental delay
  • Delayed or precocious puberty
  • Ambiguous genitalia
  • Seizures
  • Cardiac issues: cardiac failure, myocardial infarction and both high and low blood pressure
  • Skin: abnormal pigmentation, lack of pigmentation, excess body hair growth
  • Some childhood cancers
  • Hematological issues: low platelets, low red cell count, splenomegaly and lymphadenopathy
  • Diabetes
  • Musculoskeletal pain, weakness and cramping
  • Congenital malformations, especially involving facial features

 

In part 2 of this article: treatment and prevention, and where to seek help for metabolic disorders.

 

References

 

  1. Fernandes, John; Saudubray, Jean-Marie; Berghe, Georges van den (2013-03-14). Inborn Metabolic Diseases: Diagnosis and Treatment. Springer Science & Business Media. p. 4. ISBN9783662031476
  2. Jorde, et al. 2006. Carbohydrate metabolism. Medical Genetics. 3rd edition. Chapter 7. Biochemical genetics: Disorders of metabolism. pp139-142
  3. Ogier de Baulny H, Saudubray JM (2002). “Branched-chain organic acidurias”. Semin Neonatol. 7 (1): 65–74.
  4. Rosemeyer, Helmut (March 2004). “The Chemodiversity of Purine as a Constituent of Natural Products”. Chemistry & Biodiversity 1 (3): 361–401.
  5. Mark A. Sperling (25 April 2008). Pediatric Endocrinology E-Book. Elsevier Health Sciences. p. 35.
  6. Vernon, H. (2015). Inborn Errors of Metabolism. Advances in Diagnosis and Therapy. JAMA Pediatrics. 169(8): 778-782

Bioenergetics: The Chemical Conversions of Energy Production

Bioenergetics: The Chemical Conversions of Energy Production

Annalies Corse BMedSc, BHSc

Written for and originally published by the MINDD Foundation: www.mindd.org

The concept of energy for most people on a day-to day basis is an elusive one. It is that longed for health trait, presenting itself swiftly at certain points in our day, then lost as quickly as it was gained. For many individuals with robust good health, they still want more energy. Others simply never have enough, either due to genetic conditions, chronic disease, illness or malnutrition.

While the underlying reasons for lack of energy differ from one person to the next, its synthesis is universal in all human beings. In fact, energy is manufactured in humans via the same chemical reactions used to make energy in all animals, some microorganisms and insects. In the digital age, we have instant access to information to educate ourselves or seek advice on how to have more energy, yet most people still do not attain this goal for their health and well being. It’s not as simple as taking an energy supplement or drink. For decades now, science has known how energy is synthesised by the body. It’s known as bioenergetics, the study of how the body converts food into energy. It is inextricably linked to your nutritional state. Let’s take a look at some of the finer points of bioenergetics.

Energy Currency

Food contains stored energy. When we eat, carbohydrates, lipid (fats) and proteins are broken down to supply energy to every cell of the body. Energy is constantly being used up; it is needed to think, breathe, digest, walk, mount immune responses, maintain heart rate and produce hormones (to name a mere few). Once used up, we need to supply more energy, and so we must eat.

Think of energy like currency; if you spend money and have a zero balance, you need to make money. In biochemistry, this energy currency is actually in the form of a molecule known as Adenosine triphosphate (ATP). This molecule stores huge amounts of energy within specific chemical bonds in its structure. When these bonds are broken, energy is released. To replenish ATP, and put the bonds back together, we must eat. Food is broken down into its basic molecular structure. After digestion, absorption into the bloodstream and delivery to our cells, food molecules are oxidised, broken down and transformed, eventually culminating in the regeneration of ATP. This process continues, from our beginnings as an embryo to the day we take our last breath.

Mitochondria

Any reader of science will know about mitochondria. These microscopic, bean-shaped structures are classified as organelles, which translates to ‘little organs. Organelles are present inside cells; there are several different types and all have highly specialised functions. For mitochondria, their specialist function is energy production.

The inner membrane bestows mitochondria with a highly specialised structure geared specifically for energy production; the highly folded arrangement creates a huge surface area for this to take place. Mitochondria are the site of the common catabolic pathway for ATP production. ‘Common’ means that all foods (carbohydrates, fats and proteins) can enter mitochondria to make energy, and ‘catabolic’ simply means to break down the molecular structures of carbohydrates, fats and proteins in order to yield energy.

Carbohydrates

Carbohydrates are sugars. Lactose (dairy), maltose (grains), sucrose (many foods) and starches (complex carbohydrates) are broken down via digestion to yield the three simplest sugars: fructose, glucose and galactose. These three simple sugars enter cells and are catabolised via a biochemical pathway known as glycolysis, which literally translates to ‘breaking glucose’. This pathway occurs in cells, but outside our mitochondria. Once glycolysis is complete, the final product enters the mitochondria, to begin the journey through the common catabolic pathway.

Interesting fact: when you are hungry and do not eat, your body will access glucose from your liver and skeletal muscle tissue, where we store glucose for times of starvation. Liver and muscle are quickly depleted of glucose if we do not eat.
Lipids

Lipids are an excellent source of energy. While carbohydrates are exclusively used for energy production, lipids have many other important roles to play in the body, and are not always used for energy production. Lipids are also required for cell membrane structure and insulation of nerves.

Dietary lipids (fatty acids) are digested then absorbed into the lymphatic system before entering the blood stream. Upon reaching cells, fatty acids are broken down via the biochemical pathway known as B-oxidation. Like glycolysis, the final product of B-oxidation of fatty acids then enters the common catabolic pathway for energy production.

Interesting fact: as with carbohydrates, your body can access stored lipids during starvation or when energy requirements are high. Lipids are stored in our adipose tissue. The biochemical breakdown of lipids is known as lipolysis
Proteins

Proteins are complex structures, often consisting of thousands of units of amino acids linked and coiled up together. After digestion, larger proteins no longer exist, with free amino acids being absorbed into the blood stream.

It may or may not surprise you that proteins and amino acids are not the body’s first choice of molecule to break down for energy. Like lipids, amino acids have many other roles in the body. Amino acids are needed to build every single protein structure in your body, and the list is exhaustive. Proteins are structural, and form the scaffolding of your hair, skin, bones and teeth. Proteins are globular, forming everything from your blood clotting factors, some hormones through to some neurotransmitters. Amino acids are broken down in cells, and also enter the common catabolic pathway in mitochondria for energy production.

Interesting fact: We really only use proteins as an energy fuel during starvation. Again, our body will access stored protein and use it up, particularly from skeletal muscle.

Micronutrients
Micronutrients (all the vitamins and minerals) are not catabolised to yield energy. Only the macronutrients (carbohydrates, fats and proteins) can be catabolised by the many chemical reactions of the common catabolic pathway to yield energy. This is not to say micronutrients are not important for energy production. In fact, they are essential. Every step of the common catabolic pathway is catalysed or made more efficient by a specific enzyme at each step. Put simply, enzymes require nutrient co-factors, or they simply do not function. The micronutrients essential for the common catabolic pathway include vitamins B1, B2, B3, B5 and the minerals magnesium, iron and sulphur.

In order to make and replenish energy, all of the following needs to be in place:

  • Consumption of food. You must eat to make energy, you must eat to live.
  • A great diet. All diets supply carbohydrate, protein and lipids in various proportions. Only great diets supply the micronutrient vitamins and minerals to help break them down.
  • Good digestion. You are what you eat, but even more so, you are what you absorb. We must absorb all nutrients well in order to deliver them to the blood stream and our cells.
  • Good genetics. Unfortunately, our genes control all the enzymes for the various pathways described above. Some genetic diseases directly affect specific enzymes of glycolysis, or the common catabolic pathway. Energy production is compromised, sometimes very severely in these genetic conditions. In rare situations, mitochondria themselves are not functioning properly. This specific set of genetic conditions is known as mitochondrial disorders.
  • Trying to pinpoint why you are low in energy may seem complex, but if you do not have a rare genetic condition, it’s actually rather simple. It’s a currency. If you use it, you must replenish it with food and rest. Simply eat well, with a diet high in micronutrients. Focus on having a healthy gut, not just over a quick detox or cleanse, but for the long term. Not only will you experience robust energy levels, but robust good health.

References

Ball, Hill and Scott. Introduction to Biochemistry: General, Organic and Biological, First Ed.