Water in life processes

The organism possesses tremendous capacity to survive against odds and maintain homeostasis. This is particularly true with regard to water, electrolyte and acid-base status of the body. These three are interrelated, hence they are considered together for the discussion in this chapter. Kidney actively participates in the regulation of water, electrolyte and acid-base balance.

Water and life

Water is the solvent of life. Undoubtedly, water is more important than any other single compound to life. It is involved in several body functions.

Functions of water

1. Water provides the aqueous medium to the organism which is essential for the various biochemical reactions to occur.

2. Water directly participates as a reactant in several metabolic reactions.

3. It serves as a vehicle for transport of solutes.

4. Water is closely associated with the regulation of body temperature.

Distribution of water

Water is the major body constituent. An adult human contains about 60% water (men 55–70%, women 45–60%). The women and obese individuals have relatively less water which is due to the higher content of stored fat in an anhydrous form.

A 70 kg normal man contains about 42 litres of water. This is distributed in intracellular (inside the cells 28l) and extracellular (outside the cells 14l) compartments, respectively known as intracellular fluid (ICF) and extracellular fluid (ECF). The ECF is further divided into interstitial fluid (10.5l) and plasma (3.5l).

Water turnover and balance

The body possesses tremendous capacity to regulate its water content. In a healthy individual, this is achieved by balancing the daily water intake and water output.

Water intake

Water is supplied to the body by exogenous and endogenous sources.

Exogenous water

Ingested water and beverages, water content of solid foods-constitute the exogenous source of water. Water intake is highly variable which may range from 0.5–5 litres. It largely depends on the social habits and climate. 

In general, people living in hot climate drink more water. Ingestion of water is mainly controlled by a thirst center located in the hypothalamus. Increase in the osmolality of plasma causes increased water intake by stimulating thirst center.

Endogenous water

The metabolic water produced within the body is the endogenous water. This water (300–350 ml/day) is derived from the oxidation of foodstuffs. It is

estimated that 1 g each of carbohydrate, protein and fat, respectively, yield 0.6 ml, 0.4 ml and 1.1 ml of water. On an average, about 125 ml of water is generated for 1,000 Cal consumed by the body.

Water output

Water losses from the body are variable. There are four distinct routes for the elimination of water from the body—urine, skin, lungs and feces.

Urine

This is the major route for water loss from the body. In a healthy individual, the urine output is about 1–2 l/day. Water loss through kidneys although highly variable, is well regulated to meet the body demands—to get rid of water or to retain.

Skin

Loss of water (450 ml/day) occurs through the body surface by perspiration. This is an unregulated process by the body which mostly depends on the atmospheric temperature and humidity. 

The loss is more in hot climate. Fever causes increased water loss through the skin. It is estimated that for every 1°C rise in body temperature, about 15% increase is observed in the loss of water (through skin).

Lungs

During respiration, some amount of water (about 400 ml/day) is lost through the expired air. The latter is saturated with water and expelled from the body. In hot climates and/or when the person is suffering from fever, the water loss through lungs is increased.

The loss of water by perspiration (via skin) and respiration (via lungs) is collectively referred to as insensible water loss.

Feces

Most of the water entering the gastrointestinal tract is reabsorbed by the intestine. About 150 ml/day is lost through feces in a healthy individual. Fecal loss of water is tremendously increased in diarrhea.

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Brief details about Lysosomes enzyme

Lysosomes are spherical vesicles enveloped by a single membrane. Lysosomes are regarded as the digestive tract of the cell, since they are actively involved in digestion of cellular substances—namely proteins, lipids, carbohydrates and nucleic acids. 

Lysosomal enzymes are categorized as hydrolases. These include the enzymes (with substrate in brackets)—α-glucosidase (glycogen), cathepsins (proteins), lipases (lipids), ribonucleases (RNA). The lysosomal enzymes are responsible for maintaining the cellular compounds in a dynamic state, by their degradation and recycling. 

The degraded products leave the lysosomes, usually by diffusion, for reutilization by the cell. Sometimes, however, certain residual products, rich in lipids and proteins, collectively known as lipofuscin accumulate in the cell. 

Lipofuscin is the age pigment or wear and tear pigment which has been implicated in ageing process. As the cell dies, the lysosomes rupture and release hydrolytic enzymes that results in post-morteum autolysis. 

The digestive enzymes of cellular compounds are confined to the lysosomes in the best interest of the cell. Escape of these enzymes into cytosol will destroy the functional macromolecules of the cell and result in many complications. The occurrence of several diseases (e.g. arthritis, muscle diseases, allergic disorders) has been partly attributed to the release of lysosomal enzymes. 

Inclusion cell (I-cell) desease is a rare condition due to the absence of certain hydrolases in lysosomes. However, these enzyme are syntherized and found in the circulation. I-cell disease is due to a defect in protein targetting, as the enzymes cannot reach lysosomes.

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Introduction of Biochemistry

Biochemistry, also called biological chemistry.

Father of modern biochemistry – Carl Alexander Neuberg

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Biochemistry is the study of chemical processes within and relating to living organisms.

Biochemistry is the application of chemistry to the study of biological processes at the cellular and molecular level.

Introduction of Biochemistry Flow Chart

 Biochemistry Basics

• The Atom = nucleus + electrons

• The Molecule = a group of atoms

• A big molecules = a Macromolecule 

• A small molecules = a Micromolecule 

Application of Biochemistry 

Introduction-of-Biochemistry Flow Chart

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Urea cycle steps - in detailed

1. Synthesis of carbamoyl phosphate : Carbamoyl phosphate synthase I (CPS I) of mitochondria catalyses the condensation of ions with CO2 to form carbamoyl phosphate. This step consumes two ATP and is irreversible, and rate-limiting. CPS I requires N-acetylglutamate for its activity. Another enzyme, carbamoyl phosphate synthase II (CPS II)— involved in pyrimidine synthesis—is present in cytosol. It accepts amino group from glutamine and does not require N-acetylglutamate for its activity.

2. Formation of citrulline : Citrulline is synthesized from carbamoyl phosphate and ornithine by ornithine transcarbamoylase. Ornithine is regenerated and used in urea cycle. Therefore, its role is comparable to that of oxaloacetate in citric acid cycle. Ornithine and citrulline are basic amino acids. (They are never found in protein structure due to lack of codons). Citrulline produced in this reaction is transported to cytosol by a transporter system. 

Urea cycle steps - in detailed 

3. Synthesis of arginosuccinate : Arginosuccinate synthase condenses citrulline with aspartate to produce arginosuccinate. The second amino group of urea is incorporated in this reaction. This step requires ATP which is cleaved to AMP and pyrophosphate (PPi). The latter is immediately broken down to inorganic phosphate (Pi).

4. Cleavage of arginosuccinate : Arginosuccinase cleaves arginosuccinate to give arginine and fumarate. Arginine is the immediate precursor for urea.

Fumarate liberated here provides a connecting link with TCA cycle, gluconeogenesis etc.

5. Formation of urea : Arginase is the fifth and final enzyme that cleaves arginine to yield urea and ornithine. Ornithine, so regenerated, enters mitochondria for its reuse in the urea cycle. Arginase is activated by Co2+ and Mn2+. Ornithine and lysine compete with arginine (competitive inhibition).

Arginase is mostly found in the liver, while the rest of the enzymes (four) of urea cycle are also present in other tissues. For this reason, arginine synthesis may occur to varying degrees in many tissues. But only the liver can ultimately produce urea.

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Overall energy consumed during the urea cycle

The urea cycle is irreversible and consumes 4 ATP. Two ATP are utilized for the synthesis of carbamoyl phosphate. One ATP is converted to AMP and PPi to produce arginosuccinate which equals to 2 ATP. Hence 4 ATP are actually consumed.

Overall energy consumed during the urea cycle

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How to Dispose of urea from the body

Urea produced in the liver freely diffuses and is transported in blood to kidneys, and excreted. 

A small amount of urea enters the intestine where it is broken down to CO2 and NH3 by the bacterial enzyme urease. This ammonia is either lost in the feces or absorbed into the blood. In renal failure, the blood urea level is elevated (uremia), resulting in diffusion of more urea into intestine and its breakdown to NH3. 

Hyperammonemia (increased blood NH3) is commonly seen in patients of kidney failure. For these patients, oral administration of antibiotics (neomycin) to kill intestinal bacteria is advised.

How to Dispose of urea from the body 

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What is the clinical significance of urea in the blood

In healthy people, the normal blood urea concentration is 10-40 mg/dl. Higher protein intake marginally increases blood urea level, however this is well within normal range. About 15–30 g of urea (7–15 g nitrogen) is excreted in urine per day.

Blood urea estimation is widely used as a screening test for the evaluation of kidney (renal) function. It is estimated in the laboratory either by urease method or diacetyl monoxime (DAM) procedure. 

What is the clinical significance of urea in the blood 

Elevation in blood urea may be broadly classified into three categories.

1. Prerenal : This is associated with increased protein breakdown, leading to a negative nitrogen balance, as observed after major surgery, prolonged fever, diabetic coma, thyrotoxicosis etc. In leukemia and bleeding disorders also, blood urea is elevated.

2. Renal : In renal disorders like acute glomerulonephritis, chronic nephritis, nephrosclerosis, polycystic kidney, blood urea is increased.

3. Post-renal : Whenever there is an obstruction in the urinary tract (e.g. tumors, stones, enlargement of prostate gland etc.), blood urea is elevated. This is due to increased reabsorption of urea from the renal tubules. 

The term ‘uremia’ is used to indicate increased blood urea levels due to renal failure. Azotemia represents an elevation in blood urea/ or other nitrogen metabolites which may or may not be associated with renal diseases.

What is the clinical significance of urea in the blood 

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Basics of Urea cycle

Urea is the end product of protein metabolism (amino acid metabolism). The nitrogen of amino acids, converted to ammonia, is toxic to the body. It is converted to urea and detoxified. As such, urea accounts for 80–90% of the nitrogen containing substances excreted in urine.

Urea is synthesized in liver and transported to kidneys for excretion in urine.

Urea cycle is the first metabolic cycle that was elucidated by Hans Krebs and Kurt Henseleit (1932), hence it is known as Krebs-Henseleit cycle. The individual reactions, however, were described in more detail later on by Ratner and Cohen.

Urea has two amino (−NH2) groups, one derived from NH3 and the other from aspartate. Carbon atom is supplied by CO2. Urea synthesis is a five-step cyclic process, with five distinct enzymes. The first two enzymes are present in mitochondria while the rest are localized in cytosol.

Outline of urea cycle 

Basics of Urea cycle

Note : In the synthesis of urea one amino group comes from ammonium ion while the other is from aspartate; carbon is derived from CO2.

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