Purine metabolism | Importance in human physiology

Purine metabolism | Importance in human physiology

https://commons.wikimedia.org/wiki/File:Purine-3D-balls.png

Purine metabolism | Importance in human physiology

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Purine nucleotide cycle

It is a metabolic pathway that utilizes (IMP) inosine monophosphate and aspartate to produce fumarate and ammonia. The purine nucleotide cycle regulates adenine nucleotide levels and promotes the release of amino acids and ammonia. The purine nucleotide cycle was first explained by John Lowenstein for its role in glycolysis, Kreb’s cycle, and amino acid catabolism.

The purine nucleotide cycle has three basic enzyme-catalyzed steps.

Step 1: The purine nucleotide (Ex. AMP; Adenosine monophosphate) undergoes a deamination reaction to produce (IMP) inosine monophosphate. This reaction takes place in the presence of an enzyme named AMP deaminase.

AMP + H2O –> IMP + NH4+

Step 2: The IMP (inosine monophosphate) formed in the previous step combines with aspartate to form adenylosuccinate. This step is operated at the expense of energy (GTP). The enzyme adenylosuccinate synthase catalyzes this step.

Aspartate + IMP + GTP –> Adenylosuccinate + GDP + Pi (Inorganic phosphate)

Step 3: The adenylosuccinate formed in step 2 breaks down to form Adenosine monophosphate (AMP; the substrate of step 1) and Fumarate. This step is catalyzed by the enzyme known as adenylosuccinate lyase.

Important Note: The fumarate formed in this step is often utilized by tumor/cancer cells in place of oxygen as a terminal electron acceptor.

Adenylosuccinate –> Fumarate + AMP

Purine degradation

In our bodies, purines are continuously synthesized and degraded in the different biochemical pathways. Purine degradation occurs in a multi-step process:

Step 1: Nucleic acids are digested to produce mononucleotides (monomeric purines). The enzymes catalyzing this type of reaction are known as nucleases. 

DNA/RNA (containing bound purines) –> Mononucleotides (a solitary and monomeric form of purine

Step 2: mononucleotides are converted into nucleotides such as AMP (Adenosine monophosphate). This reaction occurs in an enzyme known as 5′ nucleotidase. 

Mononucleotides –> Nucleotides

Step 3: Nucleotides are then converted into free nitrogenous bases in the presence of enzyme nucleoside phosphorylase.

Nucleotides –> Free nitrogenous bases.

Purine metabolism
Figure (Purine metabolism): Purine degradation https://commons.wikimedia.org/wiki/File:Nuc_acid_deg.png

Purine amino acid

The free nitrogenous bases formed in the purine degradation step then undergo the deamination process to form xanthine and hypoxanthine in a series of biochemical reactions. These xanthine and hypoxanthine are generally known as purine amino acids. Later, these purine amino acids are converted into uric acid and further converted into urea. The complete purine degradation pathway consists of the following steps:

Step 1: Conversion of AMP (Adenosine monophosphate) into Inosine

This conversion can be completed with two possible pathways inside the body.

Pathway 1: AMP is converted into IMP (Inosine monophosphate) by the enzyme AMP aminohydrolase. Later, this IMP is converted into Inosine by the 5’-Nucleosidase enzyme.

AMP–> IMP –> Inosine

Pathway 2: AMP is converted into Adenosine by enzyme 5’-nucleotidase. Adenosine is then transformed into Inosine by the enzyme Adenosine deaminase’s action.

AMP –> Adenosine –> Inosine

Step 2: conversion of Inosine into Hypoxanthine. The enzyme nucleoside phosphorylase catalyzes this reaction. 

Inosine –> Hypoxanthine

Step 3: Conversion of Hypoxanthine into Xanthine. This reaction is catalyzed by the enzyme Xanthine Oxidase.

Hypoxanthine –> Xanthine

Step 4: Conversion of Xanthine into Uric Acid. This reaction is also catalyzed by the enzyme Xanthine Oxidase. This enzyme is present in most animal tissues, but it is present in the highest amount in the liver.

Xanthine –> Uric Acid

Step 5: Conversion of Uric Acid into Allantoin. This reaction is catalyzed by the enzyme Uricase. Uricase is not present in every tissue of the body.

Uric Acid –> Allantoin

This allantoin can be further converted into urea by the following process:

Allantoin –> Allantoic acid –> Glyoxylic Acid –> Urea

Purine table

The purine table provides information about the total purine content in a food substance. Total purine content is generally reported in mg of uric acid produced per 100 grams of a food substance.

Food SubstancePurine Content (mg of Uric Acid/100 g food Substance)
High Purine Content Foods Substances
Sheep’s Spleen773
Ox Liver554
Mushroom488
Moderate Purine Content Food Substances
Trout Fish297
Chicken Breast (with skin)175
Soya Beans190
Low Purine Content Food Substances
Apricot73
Almond37
Apple14
Table (Purine metabolism): Purine content in various food items

Purine to purine mutation

When a purine nucleotide is displaced or replaced by another purine nucleotide in a DNA strand, say, for instance, if adenine is replaced by guanine (A –> G) or guanine is replaced by adenine (G –> A). This phenomenon will be known as purine to purine mutation. It will be much more accurate to say it a purine to purine transition. Although such transitions also occur in pyrimidines, when thymine is replaced by cytosine (T –> C) or a cytosine is replaced by thymine (C –> T), this phenomenon will be known as pyrimidine to pyrimidine mutation/transition. Generally, 2/3rd of all (SNPs) single nucleotide polymorphisms are transitions.

The main causes of such transitions are tautomerization and oxidative deamination. For example, the possibility of transition in 5-methylcytosine is more than the unmethylated cytosine because 5-methyl cytosine is more likely to undergo spontaneous oxidative deamination. 

Another phenomenon known as transversion takes place in the DNA. In this phenomenon, a purine can be replaced by pyrimidine and vice versa. For example, an adenine can be replaced by thymine or cytosine. Transitions are more common in the genome as compared to transversion.

Purine metabolism | Importance in human physiology
Figure (Purine metabolism): Transition and transversion scheme
https://commons.wikimedia.org/wiki/File:All_transitions_and_transversions.svg

Purine metabolism disorder

As we have discussed in the article that the purines and their derivatives play a key role in various biochemical pathways and processes like cell signaling, cellular respiration, protein synthesis, and DNA/RNA production. Impairments and deficiency in the purine production result in various metabolic disorders such as:

Adenosine deaminase deficiency: Adenosine deaminase is the enzyme involved in converting adenosine into inosine and deoxyadenosine into deoxyinosine. The deficiency of adenosine deaminase causes adenosine retention inside the body in higher amounts. As a result, the kinases present inside the cell converts this excess adenosine into deoxyribonucleotide (dATP) and ribonucleotide (ATP). Increased dATP levels inhibit the enzyme ribonucleotide reductase, which ultimately results in the lesser production of deoxyribonucleotides and hence slows down the DNA replication process. Immune cells are more likely to get affected by adenosine deaminase deficiency, and hence it compromises our body’s immunity and makes the individual immunodeficient.

Purine nucleoside phosphorylase deficiency: It is an extremely unusual autosomal recessive condition for the gene coding the enzyme purine nucleoside phosphorylase. This enzyme’s deficiency brings about T-cell dysfunctions, adverse neurological conditions, and immunodeficiency. A majority of individuals develop ataxia and developmental delay as well.

Myoadenylate deaminase deficiency: the conversion of AMP to inosine and ammonia occurs in the presence of an enzyme known as myoadenylate deaminase. This deficiency doesn’t have any specific symptoms, but it is recognized and diagnosed by frequent muscular crampings during exercise. The frequency of cramping varies from person to person due to variations in different individuals’ muscle phenotypes. 

Purine DNA

In the universal genetic system, a purine always base pairs with pyrimidine. Still, under exceptional conditions, scientists have also found several derivatives of purines paired with each other to form short DNA helices. For example, guanine and 2,6-diamino purine can pair with isoguanine and xanthine. 

Conclusions

In this article on purine metabolism we have discussed about the important aspects of metabolism of purines, their precursors and degradation products. For more information on purines click here

FAQs

Q1. how purine nucleotides are degraded

Answer: Purines are degraded in a biochemical pathway containing the following basic steps:

Step 1: 

AMP (Adenosine monophosphate) –> Adenosine

GMP (Guanosine monophosphate) –> Guanosine

Step 2: 

Adenosine –> Hypoxanthine (keto form)

Guanosine –> Guanine

Step 3: 

Hypoxanthine –> Xanthine

Guanine –> Xanthine

Now afterward, all steps are common.

Step 4:

Xanthine –> Uric acid

Step 5:

Uric acid –> Urea/Allantoin/Urea/Ammonium ions

Q2. Is soy protein powder high in purine?

Answer: Soy protein (obtained from soya beans, botanical name: Glycine max) is considered a complete protein source as it contains every essential amino acid in significant amounts. Essential amino acids are needed for the normal growth and development of children and infants. The soy protein powder has nutritional entities quite similar to the nutritional entities of milk.

Soy proteins are free from cholesterol, saturated fats, and the total fat content is very less. Soy proteins are usually taken as food supplements to increase the diet’s nutrient density.

Soy proteins come under the category of moderate purine-containing foods. It contains 190 mg of Uric Acid/100 g food Substance (standard unit to measure purine content).

Q3. Example of Purine rich foods –

Answer: Purines rich food are like lentils, beans, cauliflower, green peas, spinach, mushrooms, asparagus, sardine, lamb, pork, beef, dal, beans, etc. 

Purine metabolism | Importance in human physiology
Figure (Purine metabolism): Purine rich foods https://commons.wikimedia.org/wiki/File:Various_legumes.jpg

Q4. Why is hydroxyurea listed as inhibiting both pyrimidine and purine synthesis?

Answer: Hydroxyurea inhibits the rate-limiting step of the de novo purine and pyrimidine biosynthesis by inhibiting a key enzyme known as ribonucleotide reductase. 

Q5. How are the atoms numbered in purine and pyrimidine?

Answer: Atoms in purine and pyrimidine are numbered in such a way.

purine
Figure (Purine metabolism): Atom numbering in purine (A) and pyrimidine (B)
https://commons.wikimedia.org/wiki/File:Purin_num2.svg
https://commons.wikimedia.org/wiki/File:Pyrimidine_2D_numbers.svg

About Dr. Abdullah Arsalan

Purine metabolism | Importance in human physiologyI am Abdullah Arsalan , Completed my PhD in Biotechnology. I have 7 years of research experience. I have published 6 papers so far in the journals of international repute with an average impact factor of 4.5 and few more are in consideration. I have presented research papers in various national and international conferences. My subject area of interest is biotechnology and biochemistry with special emphasis on Protein chemistry, enzymology, immunology, biophysical techniques and molecular biology.

Let's connect through LinkedIn(https://www.linkedin.com/in/abdullah-arsalan-a97a0a88/) or Google scholar(https://scholar.google.co.in/citations?user=AeZVWO4AAAAJ&hl=en).

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