What is the specific relationship between Prehormones, Prohormones and PreProHormones?

Question

What is the basic sequence of pre-, pro- and prepro- hormones leading to the formation of the final mature and active hormone?

I am asking because this PowerPoint slide in my Endocrinology Introductory course makes no sense to me. What I understood is that PreProHormones are the long precursors, which are spliced and cut to form pro-hormones, and then (I don’t know what happens) it becomes a prehormone, which is activated in the target cell into a mature hormone.

Is this correct (I know it’s not) and can you help me understand their relationship with each other?

Answer 1

These terms do not appear to be used consistently in the literature

In this classification, it seems they are possibly using prohormones specifically to indicate protein/peptide precursors to peptide hormones (similar to the term "proenzyme"), and prehormone for non-peptide hormone precursors. In this terminology, prohormones will always be a longer peptide chain than the hormone, and the hormone is formed by proteolysis. In that case, preprohormones are just peptides that are cut to make a prohormone, so they are longer chains than the prohormones.

It's also possible they are intending to separate based on where the conversion takes place, and a prohormone is modified to the final form in the source tissue, whereas a prehormone is released and then modified in target tissue. An example from an old paper, Baird et al 1963:

Emmens [1] has defined a prohormone as a substance which exerts its biological effect by peripheral conversion to a more active compound.

...

Prehormones may be defined as substances normally present in the body and usually secreted by endocrine glands, which have little or no biological potency themselves but are converted peripherally to more active compounds

I don't think these delineations are particularly consistent from author to author... T4 is called a prohormone, too, sometimes, and at least in Google Scholar appears with that word much more often than "prehormone".

Some urge that the delineation is on whether the modification occurs locally or elsewhere; for example this paper argues T4 should not be considered a prohormone because a prohormone is something produced and converted to the final hormone form locally, in the same gland, whereas prehormones are modified to their final form in target tissues.

Yet another case, this paper refers to a peptide hormone where they call the longest chain "prehormone" which is then shortened to a "prohormone" which is finally shortened to the final product.

For your course, I'd focus on whatever distinction your textbook/instructor wants to make, but for the rest of life (and this is general advice for all terms in biology) I'd advise:

1. Make sure you know the basis of what you're being taught, not just the term. Most terminology in biology is just labels, you cannot reason backwards from the term to learn about the world, the term is just a shorthand to cluster some concepts together to organize communication and knowledge.

2. Recognize that terminology is not consistent and you always need to clarify what is specifically meant. Authors of papers and textbooks are not necessarily consistent, as they may have different focuses and values. See also https://en.wikipedia.org/wiki/Lumpers_and_splitters for one cause of this, and https://xkcd.com/927/ for one result when people try to "fix" things to be more standard.

Answer 2

I agree with Bryan Krause that the terms are used inconsistently in the literature. However, at least to a subset of authors (and to me), the biologic difference is clear.

Preprohormones

Preprohormones are peptide hormones that have just been translated from their mRNA.

Rehfeld provides an excellent review of many types of peptide hormones (2004. PMID 9587068). However, here is a more accessible figure from Marshall and colleagues (2013. PMID 23742999):

^{Figure 1 from Marshal et al 2013 available here.}

As we can see, preprogastrin is converted to progastrin by the activity of a signal peptidase that removes the localization signal.

Prohormones

Prohormones are peptide hormones that have had their signal peptide removed. They need further modifications to become biologically active.

Progastrin, like many other peptide hormones need further post-translational modifications including by sulfotransferases. Once these modifications are complete, the prohormones undergo proteolytic cleavage by peptidases to generate biologically active hormones. As a fun aside, there is some evidence that preprogastrin actually has a small amount of biologic activity (Dockray et al 2001. PMID 11181951), so this further throws the distinction into disarray.

Prehormone

In contrast to peptide hormones, small molecule hormones like 25-OH vitamin D, are initially excreted as biologically inactive small molecules that require conversion in peripheral tissues (Vieth 2004. PMID 15225841). With titles like "Why "Vitamin D" is not a hormone", you can see this is a touchy subject for some authors.

The problem that Bryan Krause notes is that many authors seem to use prehormone and prohormone interchangeably for ultimate small molecule hormones.