Metabolism

Vitamin B12: Function and Disease

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Vitamin B12 and its derivatives serve many roles in the body. It functions primarily as a co-factor to help enzymes perform their molecular reactions. It is composed of the metal cobalt, which is coordinated to a large corrin ring structure composed of carbon and nitrogen atoms. Several important biochemical reactions in which vitamin B12 is a crucial component include:

(1) The conversion of odd chain fatty acids (specifically propionate) into succinate.
(2) The conversion of homocysteine into methionine via methyl group donation.

In the first reaction above B12 serves as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts the odd chain fatty acid L-methylmalonyl-CoA into succinyl-CoA. Succinyl-CoA can then enter the citric acid cycle (Krebs cycle).

In the second reaction vitamin B12 serves as a methyl donor (ie: a "-CH3" unit) allowing the conversion of homocysteine into methionine. Interestingly, this reaction also requires a form of vitamin B9 (aka: folate or folic acid) known as N-methyltetrahydrofolate. The reason this reaction is important is because methionine will eventually go on to form S-adenosylmethionine, which is an important contributor of single carbon fragments to various other molecules.

Additionally, vitamin B12 is needed to convert N-methyltetrahydrofolate back into tetrahydrofolate, which serves as a cofactor in a slew of other important biochemical reactions.

Role in Disease

Patients typically become deficient in vitamin B12 in one of three ways: strict vegan diets, an autoimmune condition known as pernicious anemia, or impaired absorption via the gut.

Vitamin B12 is found mainly in animal products and vegans may become deficient if they fail to supplement. Patients with pernicious anemia have antibodies that attack the cells in the stomach that secrete a molecule (intrinsic factor), which helps the intestine absorb B12 from the diet. Any damage to the gut lining (ie: inflammatory bowel disease, celiac disease, etc.) can also cause impair absorption of B12.

Deficiencies of any cause usually take several years to develop because excess vitamin B12 is stored in the liver. These stores can last several years before becoming depleted.

When a person’s vitamin B12 level is low it can cause the accumulation of odd chain fatty acids. These are thought to "gunk-up" cellular membranes. This is most noticeable in the nervous system, and can result in neurological signs and symptoms including numbness and tingling, loss of proprioception (ie: the ability to "feel" where your limbs are in space), and difficulty with coordination. In its most severe form a condition known as subacute combined degeneration of the spinal cord can occur.

Vitamin B12 deficiency can also cause a megaloblastic anemia. This occurs because rapidly dividing cells in the bone marrow require a constant supply of tetrahydrofolate for methylation reactions in order to produce enough DNA. When B12 is deficient, N-methyltetrahydrofolate cannot be converted back to tetrahydrofolate. When this occurs all of the tetrahydrofolate gets trapped in the N-methyltetrahydrofolate form, which is not used as a methyl donor in nucleotide synthesis. The resulting DNA deficiency causes red blood cells to exit the bone marrow deformed, dysfunctional, and larger than normal (hence the term "megalo"-blastic anemia).

There is no evidence that excess vitamin B12 causes any significant health problems. It is well excreted in the urine.

Diagnosis

Deficiencies of vitamin B12 are diagnosed by measuring the amount of B12 in the blood. However, "normal" B12 levels do not necessarily rule out B12 deficiency, making this test less than useful.

Other blood tests that are often sent include methylmalonyl-CoA and homocysteine levels. Both of these will be elevated in B12 deficiency since the vitamin is necessary for the enzymatic conversion of these molecules to succinyl-CoA and methionine, respectively.

Although rarely used today, another test called the Schilling test can be performed. It involves several steps in which radiolabelled B12 is given orally. If the patient is having difficulty absorbing B12 because of either intrinsic factor deficiencies or intestinal problems the Schilling test will be able to differentiate the cause.

Treatment

Treatment of vitamin B12 deficiency is, you guessed it, giving the patient B12. Patients with pernicious anemia or intestinal absorption problems are given the vitamin intramuscularly. Other patients can supplement with oral forms.

Overview

Vitamin B12, also known as cobalamin, is important in several cellular reactions including the conversion of odd chain fatty acids into succinate and the replenishing of tetrahydrofolate (a form of vitamin B9 or folate). Deficiencies may occur in those who are vegan, have pernicious anemia, or have intestinal absorption problems. Diagnosis is made by measuring blood B12, homocysteine, and methylmalonyl-CoA levels. Treatment is with supplementation, either orally or intramuscularly.

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Thiamine (Vitamin B1): Wernicke-Korsakoff and Beriberi

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Vitamin B1 (thiamine) and its derivatives serve many roles in the body. It functions primarily as a co-factor to help enzymes perform their molecular reactions. Several important biochemical reactions in which thiamine plays a crucial role include:

(1) Conversion of pyruvate to acetyl-CoA.
(2) Conversion of α-ketoglutarate to succinyl-CoA.
(3) Conversion of glyceraldehyde-3-phosphate to ribose-5-phosphate.
(4) It is used by the enzyme branched-chain α-keto acid dehydrogenase.

All of these reactions are crucial to human biochemistry. The conversion of pyruvate to acetyl-CoA feeds important molecules into the Krebs cycle, which allows the cell to produce energy.

The conversion of α-ketoglutarate to succinyl-CoA is necessary for the Krebs cycle to continue “spinning”. Without vitamin B1 (thiamine) the cycle would slow resulting in decreased energy production.

Thiamine is also important in the production of NADPH via the pentose phosphate pathway. NADPH plays a crucial role in biochemistry because it donates its electron pairs to numerous anabolic reactions.

The breakdown of branched chain amino acids such as valine, isoleucine, and leucine are also dependent on thiamine. The product that results from the breakdown of these amino acids are α-keto acids. They can also be fed into the Krebs cycle to replete molecules in the pathway that may have been siphoned off for other purposes. Maple syrup urine disease is a disorder of branched chain amino acid catabolism.

Since thiamine is involved in many energy producing pathways it is found abundantly in tissues that produce and use lots of energy. These include, but are certainly not limited to, the brain, muscle, and liver.

Role in Disease

Thiamine is a water soluble vitamin that is not actively stored in the body. It therefore must be obtained in the diet. Deficiencies can cause numerous disorders.

One such disorder is Wernicke-Korsakoff’s syndrome. It is seen in chronic alcoholics who may not be obtaining adequate nutrition. In Wernicke’s encephalopathy patients present with nystagmus (ie: jerky eye movements), ophthalmoplegia (ie: inability to move the eyes), and ataxia (ie: a wobbly unsteadiness).

These patients are often very confused. If Wernicke’s encephalopathy is left untreated it can progress to Wernicke-Korsakoff’s syndrome, in which the patient also develops short term memory problems and confabulations (ie: making up stories that aren’t true).

Another disease of thiamine deficiency is known as beriberi. There are numerous forms of this disease. It can affect infants who are being breast fed by thiamine deficient mothers, or who are receiving formulas with inadequate thiamine. In its worst case, infantile beriberi can manifest as severe heart problems.

Beriberi can also affect adults. The adult form exists in two types: wet and dry. Dry beriberi refers to the development of symmetric neuropathies (ie: damage to the peripheral nerves). Both sensory and motor nerves can be involved, and it tends to affect the parts of the nerve furthest from the spinal cord (ie: near the hands and feet). Wet beriberi is the combination of neuropathy plus heart problems, which can range in severity from cardiomegaly (ie: an enlarged heart) to congestive heart failure.

There is no evidence that excess thiamine (vitamin B1) causes any significant health problems. It is well excreted by the kidneys.

Diagnosis

Deficiencies of vitamin B1 (thiamine) are diagnosed by adding the vitamin to a preparation of the patient’s red blood cells. An increase in the activity of the transketolase enzyme is diagnostic of deficient levels.

Treatment

Treatment of thiamine deficiency is, you guessed it, giving the patient thiamine. If the patient has significant disease such as Wernicke’s encephalopathy thiamine can be given IV. Otherwise, oral supplementation and/or "prescribing" a diet rich in thiamine can be used to replenish any deficiencies.

Overview

Vitamin B1, also known as thiamine, is a vital component of numerous cellular reactions, especially those involving carbohydrate and amino acid catabolism (ie: breakdown). When deficiencies exist, several different diseases can occur. They include, but are not limited to, Wernicke-Korsakoff’s syndrome and beriberi. There are no known problems with excessive levels of thiamine since excess vitamin is efficiently excreted in the urine. Diagnosis of deficiencies are made by adding the vitamin to a preparation of the patient’s red blood cells. An increase in the activity of transketolase, an enzyme that relies on thiamine as a co-factor, is considered diagnostic of deficiency.

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Carbs, Fats, and Proteins: How the Body Burns Fuel

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Introduction

In its simplest terms, metabolic biochemistry is “fuel in, energy out”. The energy gained from burning fuel (ie: food) is used to drive all the processes going on in your body. These include the building of proteins, DNA (your genetic material), and fat, as well as mechanical things like muscle contraction.

Fuel for the human body takes three basic forms: carbohydrates (sugars), protein, and fat. Humans are capable of burning all three of these fuels, but do so at different times, rates, and under different circumstances. Using an extreme example, under starvation conditions the body burns its fat stores. Once fat stores are depleted the body begins digesting non-essential proteins and then essential proteins, which ultimately leads to organ damage and death. Thankfully, the body is relatively efficient and uses the best available fuel first before it has to tap into essential reserves.

Carbohydrates

Let’s start by discussing carbohydrates. Carbohydrates, or “carbs”, are simply sugar molecules linked to one another in varying arrangements. For example, starch, the most important carbohydrate in the human diet, is nothing more than numerous glucose molecules linked together in a long strand. Potatoes are an excellent example.

Another example of a carbohydrate is glycogen. Glycogen is how humans store excess glucose (a single sugar molecule) for later use. Unlike starch, which is a long chain of individual glucose molecules, glycogen is a highly branched structure that allows the body to rapidly cleave off individual sugar molecules to be burned for energy.

Carbohydrates can be further broken down into 2 categories: simple and complex. We’ve all heard of the term “complex carbohydrates”, which is a fancy way of saying multiple sugar molecules linked together in a complicated way. Contrarily, a simple carbohydrate is merely a few (usually 1 to 3) sugar molecules linked together.

Why make the distinction between simple and complex carbs? For starters, simple carbohydrates are rapidly absorbed by the gut and enter the bloodstream very quickly. Candy bars are a great example! If you need a quick boost of energy unwrap a Snickers®!

The problem is that since simple carbs enter the bloodstream so rapidly they get metabolized quickly. This causes you to lose that energy boost fast, which is why you often feel “de-energized” an hour or so after eating "junk food". In contrast, complex carbs get degraded by the gut much less rapidly, and therefore slowly trickle into the bloodstream. This gives you a more sustained, but less pronounced energy boost. Whole grains are a great example of complex carbs.

Why all the hub-bub about carbohydrates? Because they are, for the most part, the first energy source that is utilized during exercise. This forms the basis behind “carbo loading”, or eating a meal rich in carbohydrates the night before, or morning of, a planned work out. During exercise, the body will then utilize the individual sugar molecules in the carbohydrates to provide energy for your muscles and brain. Once you run out of sugar (or the form that humans store it in, glycogen) your body turns to the other fuel sources, namely, protein and fat.

Fats

The next fuel that gets burned is fat. All human beings have a certain percentage of body weight that is fat. From an evolutionary stand point this is advantageous. During times of drought or famine there was not enough food to provide reliable carbohydrate or protein, and thus humans survived by “burning” their fat stores. In biochemical terms, fat is nothing more than long chains of carbon atoms linked together. Suffice it to say that it is the carbon in the fat that gets utilized to form energy that your muscles and other body tissues use.

Why not burn fat first? Because fat is not as efficient an energy provider as sugar. This is the reason that endurance athletes, a few hours into a work out, hit the proverbial “wall”. The wall represents the point where they have burned up all the carbohydrate in their body, and are now running on fat reserves. The decreased amount of energy gained per unit of fat, when compared to what you get with carbs, results in a relative feeling of fatigue.

These principles can also be used as a weight loss system. Using the basics of carbohydrate and fat metabolism it makes sense that people have difficulty losing weight when they exercise vigorously for only half an hour. This is because the quick vigorous exercise burns mostly carbohydrate stores in the liver (ie: glycogen); the body never touches its fat reserves!

In contrast, running a marathon (or a nice long walk or jog in the park) causes the body to tap into its fat reserves. This is also the idea behind exercising early in the morning before having breakfast. In the morning your body has been burning carbohydrates to keep all your organs functioning; therefore, in the morning your body has less carbohydrate available to burn because it was slowly getting eaten away during sleep. If you exercise at this point you’ll have to tap into your fat stores earlier than you normally would.

Proteins

The third and final fuel is protein. The body rarely burns protein as its sole fuel source, and when it does it is usually under conditions of starvation. Interestingly, when no carbohydrate is present in the diet, the body will use the amino acid backbones of protein to form glucose (a carbohydrate) in order to supply the brain with adequate energy.

It was once thought that protein provided the energy that athletes used during exercise. This was the basis behind the “steak-and-eggs” breakfast prior to an athletic event. This has fallen out of favor as biochemists (and athletes) now realize that the body prefers to burn carbohydrates, then fat, and finally protein if all else fails.

Overview

The three main fuel sources in humans are carbohydrates, fats, and proteins. They are used preferentially under different conditions. In general, the body burns carbohydrates, then fats, and then proteins, in that order.

It is important to realize that energy metabolism is not an "all-or-none" phenomenon. The body is constantly fine tuning the exact blend of carbohydrate, fat, and protein metabolism to ensure the appropriate supply of energy to the bodies tissues.

References and Resources

  • Champe PC. Lippincott’s Illustrated Reviews: Biochemistry. Second Edition. Lippincott-Ravens Publishers, 1992.
  • Nelson DL, Cox MM. Lehninger Principles of Biochemistry. Fifth Edition. New York: Worth Publishers, 2008.
  • Summerbell CD, Cameron C, Glasziou PP. WITHDRAWN: Advice on low-fat diets for obesity. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003640.
  • Elliott SA, Truby H, Lee A. Associations of body mass index and waist circumference with: energy intake and percentage energy from macronutrients, in a cohort of Australian Children. Nutr J. 2011 May 26;10(1):58. [Epub ahead of print]

Maroteaux-Lamy Syndrome: GAGs and Dermatan Sulfate

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Maroteaux-Lamy syndrome falls into a family of conditions called the “mucopolysaccharidoses”. This fancy term describes any disorder where patients are unable to metabolize long chains of repeating sugar units.

Another term for mucopolysaccharide is glycosaminoglycan, or “GAG”. GAGs are composed of long, repeating, un-branched sugar chains. Each repeating unit has a six carbon sugar (ie: the general term for a simple six carbon sugar is a “hexose”; glucose, mannose, galactose, etc. are specific examples) attached to another six carbon sugar that has a nitrogen group sticking off of it; the general name for a six carbon sugar with an attached nitrogen group is a “hexosamine”.

These two-sugar units, a hexose plus a hexosamine, connect to one another over and over again to form a very long chain called a glycosaminoglycan.

GAGs and mucopolysaccharides are important in the human body because they make up a significant proportion of connective tissue. Connective tissues provide support and structure to many of the organ systems. As such, the body is constantly forming, breaking down, and re-molding GAGs to provide the structural framework so that the rest of our cells can do their jobs well.

So what do GAGs have to do with Maroteaux-Lamy disease? A specific GAG known as dermatan sulfate is not broken down appropriately in patient’s suffering from this condition.

The reason these individuals are unable to break down dermatan sulfate is because they have a genetic mutation in the enzyme arylsulfatase B. In a normal person, arylsulfatase B degrades excess and unwanted dermatan sulfate; however, when the enzyme is defective it causes dermatan sulfate to build up to abnormally high levels within cells.

This excess dermatan sulfate eventually “gunks” up various organ systems and results in the characteristic signs and symptoms associated with the disease.

Signs and Symptoms

It is important to realize that there are numerous genetic mutations that can cause Maroteaux-Lamy syndrome and not all mutations are created equal! Therefore, there is a wide spectrum of signs and symptoms that may occur quickly, or slowly, depending on which particular mutation the patient has.

Most patients are short and have progressive changes in their facial features. Patients often develop early onset vision problems because their corneas become clouded by excess dermatan sulfate. Joint stiffness and skeletal abnormalities are also very common, as are heart and lung complications.

The lining of the brain and spinal cord can become excessively thick which can cause weakness secondary to spinal cord and nerve compression.

Patient’s also often have enlargement of the spleen – a condition called “splenomegaly”. It is also not uncommon for patients to have various types of hernias.

Unlike patients who suffer from some of the other mucopolysaccharidoses, people with Maroteaux-Lamy are of normal intelligence.

Diagnosis

Overall, Maroteaux-Lamy disease is more appropriately a “syndrome”, or constellation of signs and symptoms. By themselves, each sign or symptom is not diagnostic of the disorder, but when present together can support the diagnosis.

Genetic testing for mutations of the arylsulfatase B gene are done once the syndrome is suspected on clinical grounds. Additionally, urine samples contain elevated amounts of dermatan sulfate.

Treatment

Treatment consists of using a replacement enzyme known as Naglazyme® (aka: galsulfase). This enzyme performs the function of the deficient arylsulfatase B and helps in the degradation of dermatan sulfate.

Stem cell transplants can also provide the missing enzyme, but at significant risk. Unfortunately, few patients are candidates for stem cell transplant given difficulty with donor matching.

A very important component of treatment is monitoring for the development or progression of symptoms. This will allow specialists to step in and perform palliative procedures that can prevent worsening disability. For example, corneal transplants can be done to restore vision loss.

Overview

Maroteaux-Lamy is one of the mucopolysaccharidoses. It is caused by a genetic deficiency in the enzyme arylsulfatase-B, which prevents the degradation of dermatan sulfate. It presents with numerous signs and symptoms, which may be rapidly or slowly progressive depending on the specific genetic mutation. Treatment is with enzyme replacement therapies and palliative management of symptoms.

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References and Resources

  • Calleja Gero ML, González Gutiérrez-Solana L, López Marín L, et al. Neuro-imaging findings in patient series with mucopolysaccharidosis. Neurologia. 2011 Dec 15.
  • Mtar A, Charfeddine B, Braham I, et al. Maroteaux-Lamy syndrome: a case report. Ann Biol Clin (Paris). 2011 Dec 1;69(6):693-697.
  • Golda A, Jurecka A, Tylki-Szymanska A. Cardiovascular manifestations of mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome). Int J Cardiol. 2011 Jul 5.
  • Valayannopoulos V, Wijburg FA. Therapy for the mucopolysaccharidoses. Rheumatology (Oxford). 2011 Dec;50 Suppl 5:v49-v59.